Articles de revues : « Syndrome de Li-Fraumeni (LFS) »

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Giacomazzi, Cristina Rossi, Juliana Giacomazzi, Cristina B. O. Netto, Patricia Santos-Silva, Simone Geiger Selistre, Ana Luiza Maia, Viviane Ziebell de Oliveira, Suzi Alves Camey, José Roberto Goldim et Patricia Ashton-Prolla. « Pediatric cancer and Li-Fraumeni/Li-Fraumeni-like syndromes : a review for the pediatrician ». Revista da Associação Médica Brasileira 61, n^o 3 (juin 2015) : 282–89. http://dx.doi.org/10.1590/1806-9282.61.03.282.

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Summary Introduction: cancer is the second leading cause of death in children between the ages of 0 and 14 years, corresponding to approximately 3% of all cases diagnosed in Brazil. A significant percentage (5-10%) of pediatric cancers are associated with hereditary cancer syndromes, including Li-Fraumeni/Li-Fraumeni-like syndromes (LFS/LFL), both of which are caused by TP53 germline mutations. Recent studies have shown that a specific TP53 mutation, known as p.R337H, is present in 1 in 300 newborns in Southern and Southeast Brazil. In addition, a significant percentage of children with LFS/LFL spectrum tumors in the region have a family history compatible with LFS/LFL. Objective: to review clinical relevant aspects of LFS/LFL by our multidisciplinary team with focus on pediatric cancer. Methods: the NCBI (PubMed) and SciELO databases were consulted using the keywords Li-Fraumeni syndrome, Li-Fraumeni-like syndrome and pediatric cancer; and all manuscripts published between 1990 and 2014 using these keywords were retrieved and reviewed. Conclusion: although LFS/LFL is considered a rare disease, it appears to be substantially more common in certain geographic regions. Recognition of population- specific risks for the syndrome is important for adequate management of hereditary cancer patients and families. In Southern and Southeastern Brazil, LFS/ LFL should be considered in the differential diagnosis of children with cancer, especially if within the spectrum of the syndrome. Due to the complexities of these syndromes, a multidisciplinary approach should be sought for the counseling, diagnosis and management of patients and families affected by these disorders. Pediatricians and pediatric oncologists in areas with high prevalence of hereditary cancer syndromes have a central role in the recognition and proper referral of patients and families to genetic cancer risk evaluation and management programs.

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Sarac, Sanja, Zeljko Krsmanovic, Rade Milic, Tatjana Radevic, Biljana Lazovic-Popovic, Mira Vasiljevic et Momir Sarac. « Li-Fraumeni syndrome : Case report ». Vojnosanitetski pregled, n^o 00 (2022) : 36. http://dx.doi.org/10.2298/vsp211102036s.

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Introduction. Li-Fraumeni syndrome (LFS) is a hereditary familial predisposition to a wide range of certain, often rare, malignant diseases. Patients also have a heightened risk of developing secondary and even tertiary malignancies throughout lifetime. The most common are soft-tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinoma and acute leukemia. Syndrome is inherited as an autosomal dominant disorder. In most families with LFS have been identified germline mutations of tumor protein TP53 gene. To our knowledge, this is the second case report of LFS that has been reported in our country, so far. Case report. We present five members of the same family with malignant diseases typical for LFS. A woman at the age of 21 with recurrent astrocytoma and mediastinal liposarcoma. The mother of her father had breast cancer at the age of 45 and died at 52. The father's sister had osteosarcoma, died before 40. The older sister had rhabdomyosarcoma and liver cancer, died at 18. Their father was diagnosed with lung adenocarcinoma two years after the second daughter, at the age of 49. Genetic analysis identified a pathogenic, heterozygous germline mutation TP53 gene. He also has an 8-yearold daughter who has not been tested for LFS. Conclusion. Genetic analysis for LFS of all family members is required in patients with rare and multiple malignancies, frequent and early onset malignancies in the family. Screening for the detection of early cancer manifestation is key to prolonged survival in people with LFS.

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Donovan, Lauren N., Jennie Vagher, Anna Zakas, Kyle Shoger, Anne Naumer, Journey Bly, Kelcy Smith-Simmer et al. « Hematologic malignancies in Li-Fraumeni syndrome. » Journal of Clinical Oncology 42, n^o 16_suppl (1 juin 2024) : 10613. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.10613.

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10613 Background: Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome caused by mutations in the tumor suppressor gene TP53. Since its discovery, a growing list of cancers have been described in association with LFS, predominantly solid tumors. However, hematologic malignancies (HMs) cumulatively account for 4-10% of cancer diagnoses in LFS. In this study, we present the largest series of HMs in families with LFS with detailed clinical courses. Methods: This was a two-center retrospective observational cohort study conducted at the University of Utah and the University of Wisconsin-Madison with IRB approval. Cancer genetics clinic registries were reviewed to identify all families with LFS who also had a confirmed diagnosis of a HM. To meet criteria for LFS, the patient had to have a confirmed germline pathologic or likely pathologic TP53 variant. Patients with a TP53 variant of unknown significance (VUS) were also included if they met classical LFS testing criteria. Data was gathered by manual chart review of both the families’ histories and electronic health records. Results: Among the 121 families identified with LFS, 35 (29%) families had one or more HM. Of these, 17 individuals from 16 families (13%) had confirmed germline TP53 mutations. The most frequent HMs found were acute lymphoblastic leukemia (ALL) (n=6), non-Hodgkin lymphoma (NHL) (n=5), myelodysplastic syndromes (MDS) (n=3), and chronic lymphocytic leukemia (CLL) (n=2). Acute myeloid leukemia (AML), Langerhans cell histiocytosis (LCH), and chronic myeloid leukemia (CML) were each diagnosed once. Most cases were identified in adulthood (n=12, 71%). Of the 19 total HMs, the minority (n=5, 26%) were diagnosed post-cytotoxic therapy and only six (35%) individuals had received a diagnosis of LFS prior to HM diagnosis. The MDS/AML cohort (n=4) all exhibited bi-allelic inactivation of TP53. Two of these four patients achieved long term survival after matched-unrelated donor (MUD) hematopoietic stem cell transplant (HSCT). All three patients who underwent MUD donor HSCT had immune-mediated adverse events. Conclusions: In this study we found a significantly higher incidence of HMs in LFS than previously described, with a predominance of lymphoid over myeloid malignancies. The majority of patients had excellent outcomes after standard of care therapy pointing towards more favorable outcomes for patients with LFS and HMs than previously reported. We also report several unusual immune-mediated adverse events in our patients indicating possible immunogenicity of some TP53 variants. Most patients did not have prior exposure to cytotoxic treatments and were diagnosed with the HM prior to their LFS diagnosis. We also show that 38% of individuals with an HM have multiple family members with an HM, consistent with a familial HM pattern. This underscores the importance of detailed family and personal histories in HM patients found to carry a somatic TP53 variant.

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Ilic, Miroslav, Kiralj Aleksandar, Borislav Markov, Ivana Mijatov, Sasa Mijatov et Nada Vuckovic. « Li-fraumeni syndrome : A case report ». Vojnosanitetski pregled 71, n^o 12 (2014) : 1159–62. http://dx.doi.org/10.2298/vsp1412159i.

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Introduction. Li-Fraumeni syndrome (LFS) is a very rare familial disease with the predisposition to the development of malignant tumors, such as osteosarcoma, breast cancer, brain neoplasm, leukemia, and adrenal tumors. Inheritance is autosomal dominant and is caused by heterozygous mutations in the p53 gene. The diagnosis is based on clinical criteria: a person under the age of 45 years suffering from sarcoma, the closest relative younger than 45 years diagnosed with cancer and a relative of the first or second degree, which is up to 45 years, was diagnosed with cancer and was diagnosed with sarcoma at any age. Case report. The presented family with three members diagnosed with malignant disease typical for LFS suggests the need to carefully follow those diagnosed with LFS related tumor. A 24-yearold man diagnosed and treated for osteosarcoma of the maxilla died in the first year. His younger brother was submitted to surgery due to osteosarcoma of the mandible three years later, and a year later in his 24 year he had no signs of locoregional recurrence. Their mother was operated in 1996 for glioblastoma multiform brain cancer and ductal carcinoma, and died two years later at the age of 33. Conclusion. The presented family highlights the need for careful examination, inspection and notification of the risks of family members diagnosed with LFS related tumors.

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Mahin, Humaira Haider, Matthew Beck, Toni Palasovski et Sarbar Napaki. « An Uncommon Presentation of Li Fraumeni Syndrome ». Journal of Medical Research and Surgery 1, n^o 2 (18 mars 2020) : 1–3. http://dx.doi.org/10.52916/jmrs204008.

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We report a case of Li Fraumeni Syndrome (LFS), where our patient was affected by two malignancies before the age of 30: chondroblastic osteosarcoma and unilateral breast ductal carcinoma in situ. Her daughter was diagnosed with adrenocortical carcinoma at the age of four, and her mum was diagnosed with cervical cancer when she was in her 20’s. After her daughter’s cancer diagnosis, she and her family members underwent genetic testing. She and her daughter were found to have Tumour Protein 53 gene (TP53) mutation suggestive for Li Fraumeni Syndrome (LFS). Patients with LFS should be managed with a surveillance program with minimal exposure to radiation therapy due to their high risk for second primary cancer. This report will make the clinician aware of this syndrome for early diagnosis and management.

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Bougeard, Gaëlle, Mariette Renaux-Petel, Jean-Michel Flaman, Camille Charbonnier, Pierre Fermey, Muriel Belotti, Marion Gauthier-Villars et al. « Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers ». Journal of Clinical Oncology 33, n^o 21 (20 juillet 2015) : 2345–52. http://dx.doi.org/10.1200/jco.2014.59.5728.

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Purpose The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity. Patients and Methods From 1,730 French patients suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation. Results The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations. Conclusion The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.

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Kumamoto, Tadashi, Fumito Yamazaki, Yoshiko Nakano, Chieko Tamura, Shimon Tashiro, Hiroyoshi Hattori, Akira Nakagawara et Yukiko Tsunematsu. « Medical guidelines for Li–Fraumeni syndrome 2019, version 1.1 ». International Journal of Clinical Oncology 26, n^o 12 (11 octobre 2021) : 2161–78. http://dx.doi.org/10.1007/s10147-021-02011-w.

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AbstractLi–Fraumeni syndrome (LFS) is a hereditary tumor that exhibits autosomal dominant inheritance. LFS develops in individuals with a pathogenic germline variant of the cancer-suppressor gene, TP53 (individuals with TP53 pathogenic variant). The number of individuals with TP53 pathogenic variant among the general population is said to be 1 in 500 to 20,000. Meanwhile, it is found in 1.6% (median value, range of 0–6.7%) of patients with pediatric cancer and 0.2% of adult patients with cancer. LFS is diagnosed by the presence of germline TP53 pathogenic variants. However, patients can still be diagnosed with LFS even in the absence of a TP53 pathogenic variant if the familial history of cancers fit the classic LFS diagnostic criteria. It is recommended that TP53 genetic testing be promptly performed if LFS is suspected. Chompret criteria are widely used for the TP53 genetic test. However, as there are a certain number of cases of LFS that do not fit the criteria, if LFS is suspected, TP53 genetic testing should be performed regardless of the criteria. The probability of individuals with TP53 pathogenic variant developing cancer in their lifetime (penetrance) is 75% for men and almost 100% for women. The LFS core tumors (breast cancer, osteosarcoma, soft tissue sarcoma, brain tumor, and adrenocortical cancer) constitute the majority of cases; however, various types of cancers, such as hematological malignancy, epithelial cancer, and pediatric cancers, such as neuroblastoma, can also develop. Furthermore, approximately half of the cases develop simultaneous or metachronous multiple cancers. The types of TP53 pathogenic variants and factors that modify the functions of TP53 have an impact on the clinical presentation, although there are currently no definitive findings. There is currently no cancer preventive agent for individuals with TP53 pathogenic variant. Surgical treatments, such as risk-reducing bilateral mastectomy warrant further investigation. Theoretically, exposure to radiation could induce the onset of secondary cancer; therefore, imaging and treatments that use radiation should be avoided as much as possible. As a method to follow-up LFS, routine cancer surveillance comprising whole-body MRI scan, brain MRI scan, breast MRI scan, and abdominal ultrasonography (US) should be performed immediately after the diagnosis. However, the effectiveness of this surveillance is unknown, and there are problems, such as adverse events associated with a high rate of false positives, overdiagnosis, and sedation used during imaging as well as negative psychological impact. The detection rate of cancer through cancer surveillance is extremely high. Many cases are detected at an early stage, and treatments are low intensity; thus, cancer surveillance could contribute to an improvement in QOL, or at least, a reduction in complications associated with treatment. With the widespread use of genomic medicine, the diagnosis of LFS is unavoidable, and a comprehensive medical care system for LFS is necessary. Therefore, clinical trials that verify the feasibility and effectiveness of the program, comprising LFS registry, genetic counseling, and cancer surveillance, need to be prepared.

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Laverty, Brianne, Vallijah Subasri, Nicholas Light et David Malkin. « Abstract 3364 : Diagnosing Li-Fraumeni syndrome from the somatic genome ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 3364. http://dx.doi.org/10.1158/1538-7445.am2022-3364.

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Abstract Background: Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in the tumor suppressor gene TP53. LFS is estimated to occur in 1:1000 - 1:5000 people and is associated with a 80% lifetime cancer risk. This syndrome is diagnosed using familial cancer history and germline TP53 sequencing; however, clinical heterogeneity and variants of unknown significance limit diagnostic precision. Accurate diagnosis is imperative to implement surveillance for secondary malignancies and familial genetic testing. Methods: We hypothesized that LFS cancers evolve uniquely from sporadic cancers, implying that the somatic genomes of LFS patients exhibit distinct characteristics that can infer the predisposition syndrome. To investigate this, we interrogated mutational signatures, TP53 copy number, TP53 loss of heterozygosity, ploidy, and the incidence of chromothripsis in tumor compared to normal samples (blood or fibroblast) of individuals with germline TP53 mutations (n=27), somatic TP53 mutations (n=17) and WT for TP53 (n=158). We created a random forest model with 10-fold cross validation to determine if somatic features could diagnose LFS. Results: No signatures were significantly associated with LFS (Wilcoxon rank-sum test, Benjamin-Hochberg FDR correction). As previously reported in the literature, LFS compared to non-LFS cancers in our cohort were more likely to: be hyperdiploid (odds ratio (OR) = 11.83, FDR < 0.0001, Fisher exact test), have undergone TP53 loss of heterozygosity (OR = 23.15, FDR < 0.0001, Fisher exact test) and experience chromothripsis (OR = 7.76, FDR < 0.001, Fisher exact test). The area under the receiver operating curve (AUROC) for our random forest model with 10-fold cross validation was 0.90, the area under the precision recall curve (AUPRC) was 0.59, the positive predictive value (PPV) was 0.70, the negative predictive value (NPV) was 0.93 and the F1-score was 0.52. This implies that the somatic genomic features are reliable indicators of this germline syndrome. We have obtained access to a future 50 LFS samples from the Pediatric Cancer Genome Project dataset, which we hope will improve our model’s performance. Conclusion: We have developed a machine learning tool that uses somatic features to identify LFS, a germline cancer predisposition syndrome. As the importance of precision oncology becomes apparent, a tool to identify LFS patients from the somatic genome will facilitate early diagnosis. This will allow individuals to enter a surveillance program for early detection of secondary tumors, leading to improved outcomes. Citation Format: Brianne Laverty, Vallijah Subasri, Nicholas Light, David Malkin. Diagnosing Li-Fraumeni syndrome from the somatic genome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3364.

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Lammens, Chantal R. M., Neil K. Aaronson, Anja Wagner, Rolf H. Sijmons, Margreet G. E. M. Ausems, Annette H. J. T. Vriends, Mariëlle W. G. Ruijs et al. « Genetic Testing in Li-Fraumeni Syndrome : Uptake and Psychosocial Consequences ». Journal of Clinical Oncology 28, n^o 18 (20 juin 2010) : 3008–14. http://dx.doi.org/10.1200/jco.2009.27.2112.

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Purpose Li-Fraumeni syndrome (LFS) is a hereditary cancer syndrome, characterized by a high risk of developing cancer at various sites and ages. To date, limited clinical benefits of genetic testing for LFS have been demonstrated, and there are concerns about the potential adverse psychosocial impact of genetic testing for LFS. In this study, we evaluated the uptake of genetic testing and the psychosocial impact of undergoing or not undergoing a genetic test for LFS. Patients and Methods In total, 18 families with a p53 germline mutation in the Netherlands were identified. Eligible family members were invited to complete a self-report questionnaire assessing motives for undergoing or not undergoing genetic testing, LFS-related distress and worries, and health-related quality of life. Results Uptake of presymptomatic testing was 55% (65 of 119). Of the total group, 23% reported clinically relevant levels of LFS-related distress. Carriers were not significantly more distressed than noncarriers or than those with a 50% risk who did not undergo genetic testing. Those with a lack of social support were more prone to report clinically relevant levels of distress (odds ratio, 1.3; 95% CI, 1.0 to 1.5). Conclusion Although preventive and treatment options for LFS are limited, more than half of the family members from known LFS families choose to undergo presymptomatic testing. An unfavorable genetic test result, in general, does not cause adverse psychological effects. Nonetheless, it is important to note that a substantial proportion of individuals, irrespective of their carrier status, exhibit clinically relevant levels of distress which warrant psychological support.

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Stojiljković, Dejan, Ana Cvetković, Andrej Jokić, Dijana Mirčić, Sanja Mihajlović, Ana Krivokuća, Marija Đorđić Crnogorac et Lazar Glisic. « Li-Fraumeni Syndrome With Six Primary Tumors—Case Report ». Case Reports in Oncological Medicine 2024 (10 mai 2024) : 1–7. http://dx.doi.org/10.1155/2024/6699698.

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Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with a high, lifetime risk of a broad spectrum of cancers caused by pathogenic germline TP53 mutations. Numerous different germline TP53 mutations have been associated with LFS, which has an exceptionally diverse clinical spectrum in terms of tumor type and age of onset. Our patient has developed six asynchronous tumors to date: a phyllode tumor of the breast, a pheochromocytoma, a rosette-forming glioneuronal tumor (RGNT), an adrenocortical carcinoma (ACC), a ductal carcinoma of the breast, and a thymoma. The occurrence of such a number of rare tumors is sporadic even among in the population of patients living with cancer predisposition syndromes. In this instance, the omission of pretest genetic counseling and thorough family tree analysis prior to selecting the test led to the oversight of an underlying TP53 likely pathogenic mutation (classified as Class 4). This emphasizes the necessity for such counseling to prevent overlooking crucial genetic information. Neglecting this step could have had profound implications on the patient’s treatment, particularly considering the early onset and occurrence of multiple tumors, which typically raise suspicion of a hereditary component. The implications for family members must be considered.

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Papadimitriou, Dimitrios T., Constantine A. Stratakis, Antonis Kattamis, Stavros Glentis, Constantine Dimitrakakis, George P. Spyridis, Panagiotis Christopoulos, George Mastorakos, Nikolaos F. Vlahos et Nicoletta Iacovidou. « A Novel Variant in the TP53 Gene Causing Li–Fraumeni Syndrome ». Children 10, n^o 7 (30 juin 2023) : 1150. http://dx.doi.org/10.3390/children10071150.

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Li–Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome associated with germline pathogenic variants in the tumor protein p53 (TP53) gene and elevated risk of a broad range of early-onset malignancies. Patients with LFS are at risk of a second and third primary tumor. A 15-month-old girl consulted for clitoromegaly and pubic hair. Adrenal ultrasound detected a large left adrenal tumor. Left total adrenalectomy confirmed adrenocortical carcinoma. Family history revealed multiple highly malignant neoplasms at an early age across five generations, and a genetic dominant trait seemed probable. Whole-genome sequencing was performed. Multiple members of the family were found positive for a novel likely pathogenic variant (c. 892delGinsTTT, p. Glu298PhefsX48, NM_000546.6) in the TP53 gene, causing the loss of normal protein function through non-sense-mediated mRNA decay. According to the PSV1 supporting criteria and the Auto PVS1 online tool this frameshift variant: hg19/17-7577045-TC-TAAA:NM_000546.6 has a very strong, definitive clinical validity for LFS with autosomal dominant inheritance. Proper guidance resulted in timely diagnosis of a second tumor (primary osteosarcoma) in the index case and in the early detection of breast and cervical cancer in her young mother. Patients with cancer predisposition syndromes like LFS require close multidisciplinary cancer surveillance and appropriate referral to expert centers.

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Talwalkar, Sameer S., C. Cameron Yin, Rizwan C. Naeem, M. John Hicks, Louise C. Strong et Lynne V. Abruzzo. « Myelodysplastic Syndromes Arising in Patients With Germline TP53 Mutation and Li-Fraumeni Syndrome ». Archives of Pathology & ; Laboratory Medicine 134, n^o 7 (1 juillet 2010) : 1010–15. http://dx.doi.org/10.5858/2009-0015-oa.1.

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Abstract Context.—Li-Fraumeni syndrome (LFS), characterized by predisposition to early onset of a variety of malignancies, is usually associated with germline mutation of the tumor-suppressor gene, TP53. Mutation carriers are at increased risk of multiple primary tumors, many of which arise in previous radiation-therapy sites. In patients with LFS, acute myeloid leukemia is uncommon and myelodysplastic syndrome (MDS) is rare. Objective.—To evaluate the morphologic, cytogenetic, and molecular diagnostic findings of 3 unique cases of MDS arising in patients with germline TP53 mutation, 2 with classic LFS. Design.—We searched the Li-Fraumeni Syndrome Registry in the Department of Genetics at the University of Texas M. D. Anderson Cancer Center (Houston, Texas) and identified 3 patients with documented germline TP53 mutations or LFS who had developed MDS during a period of 6 years (2000–2005). The clinical, cytogenetic, and molecular diagnostic data and bone marrow aspirate smears and biopsies on all patients were reviewed. Immunohistochemical staining with antibody to p53 was also performed. Results.—Two patients met the criteria for classic LFS; one had no history of malignancy in first-degree relatives. The MDS followed chemotherapy and radiation therapy and progressed to acute myeloid leukemia in 2 patients. Cytogenetic analysis demonstrated chromosome 5 abnormalities in a complex karyotype in all cases. Two patients died, one of acute myeloid leukemia and one with glioblastoma multiforme, MDS, and persistent pancytopenia. Conclusions.—Patients with LFS may develop MDS, which is most likely therapy-related and is associated with cytogenetic markers of poor prognosis.

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Erok, Berrin, et Kenan Kıbıcı. « An aggressive locoregional orbital rhabdomyosarcoma and Li Fraumeni syndrome ». European Journal of Clinical and Experimental Medicine 19, n^o 1 (2021) : 81–85. http://dx.doi.org/10.15584/ejcem.2021.1.11.

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Introduction. Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with 10 % of the cases occuring in the orbit. Patients often present with a rapidly developing proptosis and globe displacement. Aim. We aimed to present a very rare presentation of orbital RMS, with a giant exophytic orbital mass, a very rare presentation occuring in more advanced cases. Description of the case. A 3-year old girl presented to our hospital with a rapidly enlarging tissue like ulcerative mass. Her past medical history was remarkable with the diagnosis of embryonal rhabdomyosarcoma (RMS) and treatment with chemoradiotherapy at the age of 15 months. On magnetic resonance imaging (MRI), there was a giant heterogenously enhancing mass filling the right orbit and extending to the intracranial region. Li Fraumeni syndrome (LFS) was considered due to her sister death from neuroblastoma at an early age. Cytogenetic analysis revealed mutations of p53 gene, which supported our consideration. Conclusion. RMS is a highly malignant tumor which usually occurs sporadiacally. However, some rare syndromes are associated with increased incidence of RMS, such as LFS.

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Pantziarka, Pan, et Sarah Blagden. « Inhibiting the Priming for Cancer in Li-Fraumeni Syndrome ». Cancers 14, n^o 7 (23 mars 2022) : 1621. http://dx.doi.org/10.3390/cancers14071621.

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The concept of the pre-cancerous niche applies the ‘seed and soil’ theory of metastasis to the initial process of carcinogenesis. TP53 is at the nexus of this process and, in the context of Li-Fraumeni Syndrome (LFS), is a key determinant of the conditions in which cancers are formed and progress. Important factors in the creation of the pre-cancerous niche include disrupted tissue homeostasis, cellular metabolism and chronic inflammation. While druggability of TP53 remains a challenge, there is evidence that drug re-purposing may be able to address aspects of pre-cancerous niche formation and thereby reduce the risk of cancer in individuals with LFS.

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Giovino, Camilla, Nicholas Fischer, Noel Ong, Ashby Kissoondoyal, Ran Kafri et David Malkin. « Abstract 1533 : Characterizing tumor-immune surveillance in Li-Fraumeni syndrome ». Cancer Research 84, n^o 6_Supplement (22 mars 2024) : 1533. http://dx.doi.org/10.1158/1538-7445.am2024-1533.

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Abstract Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome associated with germline TP53 mutations and increased lifetime risk of developing multiple cancers. p53, the protein encoded by TP53, plays a role in regulating various aspects of immune cell biology. Accordingly, inactivation of p53 in tumor cells shapes interactions with the immune system and influences the anti-tumor immune response. Mutation or deletion of p53 in immune cells also favors tumor development and progression. However, to date, a comprehensive study of immune cell populations and the anti-tumor immune response has not been undertaken in the context of LFS. We hypothesized that germline TP53 mutation carriers possess dysfunctional immune cells and/or immune responses, supporting LFS-associated tumor progression. Our preliminary data indicate a profound defect in tumor-immune surveillance in an LFS murine model. We observed that MC38 cancer cells develop significantly faster into tumors when injected into LFS mice (harboring a gain-of-function mutation Trp53R172H/WT) compared to wildtype (WT) control mice. Importantly, we identified significant alterations in immune cell compositions and phenotypes within the tumor microenvironment as well as immune organs using flow cytometry. We are currently using ex vivo proliferation assays and cytotoxicity assays to investigate the impact of mutant p53 on the tumor-killing ability of immune effector cells. Altogether, an improved understanding of anti-tumor immune dysfunction in the context of germline TP53 mutation may reveal the potential for innovative therapies to target different facets of the immune system to intercept cancer progression in LFS patients. Citation Format: Camilla Giovino, Nicholas Fischer, Noel Ong, Ashby Kissoondoyal, Ran Kafri, David Malkin. Characterizing tumor-immune surveillance in Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1533.

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Barlow, Jason W., Marieke Mous, Joe C. Wiley, Jennifer M. Varley, Guillermina Lozano, Louise C. Strong et David Malkin. « Germ Line BAX Alterations Are Infrequent in Li-Fraumeni Syndrome ». Cancer Epidemiology, Biomarkers & ; Prevention 13, n^o 8 (1 août 2004) : 1403–6. http://dx.doi.org/10.1158/1055-9965.1403.13.8.

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Abstract Multiple early-onset tumors, frequently associated with germ line TP53 mutations characterize the Li-Fraumeni familial cancer syndrome (LFS). LFS-like (LFS-L) families have lower rates of germ line TP53 alteration and do not meet the strict definition of LFS. This study examined 7 LFS cell lines and 30 LFS and 36 LFS-L primary leukocyte samples for mutations in the proapoptotic p53-regulated gene BAX. No germ line BAX mutations were found. A known BAX polymorphism was observed, yet there was no correlation between polymorphism frequency and TP53 status in either LFS or LFS-L. In summary, alterations of BAX are not responsible for cancers in TP53 wild-type LFS or LFS-L families.

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Messina, Raffaella, Gerardo Cazzato, Teresa Perillo, Vita Stagno, Valeria Blè, Mariachiara Resta, Francesco De Leonardis, Nicola Santoro, Francesco Signorelli et Giuseppe Ingravallo. « A Unique Case of Bilateral Thalamic High-Grade Glioma in a Pediatric Patient with LI-Fraumeni Syndrome : Case Presentation and Review of the Literature ». Neurology International 13, n^o 2 (22 avril 2021) : 175–83. http://dx.doi.org/10.3390/neurolint13020017.

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Li-Fraumeni syndrome (LFS) is a rare high-penetrance and autosomal-dominant pathological condition caused by the germline mutation of the TP53 gene, predisposing to the development of tumors from pediatric age. We conducted a qualitative systematic review following the ENTREQ (Enhancing Transparency in Reporting the Synthesis of Qualitative Research) framework. A search was made in MEDLINE/Pubmed and MeSH Database using the terms “Li-Fraumeni” AND “pediatric high-grade glioma (HGG)”, identifying six cases of HGGs in pediatric patients with LFS. We added a further case with peculiar features such as no familiar history of LFS, association of embryonal rhabdomyosarcoma and bithalamic HGG, whose immunohistochemical profile was accurately defined by Next Generation Sequencing. Knowledge synthesis and case analysis grounded the discussion about challenges in the management of this pathology in pediatric age.

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Zarubina, Kseniia I., Elena N. Parovichnikova, Vadim L. Surin, Olesia S. Pshenichnikova, Olga A. Gavrilina, Galina A. Isinova, Vera V. Troitskaya et al. « Li–Fraumeni syndrome in adult patients with acute lymphoblastic leukemia ». Terapevticheskii arkhiv 93, n^o 7 (23 juillet 2021) : 763–69. http://dx.doi.org/10.26442/00403660.2021.07.200913.

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Background. LiFraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary disorder that is characterized by an increased risk for certain types of cancer, acute lymphoblastic leukemia (ALL), particularly. Germline TP53 mutations are associated with LFS. Genetic counseling and follow-up is essential for patients with LFS and their relatives. Special therapeutic approaches are needed for treatment of oncological disease in these patients. The article presents a series of clinical cases of patients with ALL and SLF, considers general issues of diagnosis and treatment of adult patients with this hereditary genetic syndrome. Aim. Describe clinical observations of patients with acute lymphoblastic leukemia (ALL) and LFS and consider general issues of diagnosis and treatment of adult patients with LFS and ALL. Materials and methods. TP53 gene mutations were screened using Sanger sequencing in 180 de novo patients with Ph-negative (B- and T-cell) and Ph-positive ALL treated by Russian multicenter protocols (ALL-2009, ALL-2012, ALL-2016) at the National Research Center for Hematology, Moscow, Russia, and at the hematology departments of regional clinics of Russia (multicenter study participants). Results. TP53 gene mutations were found in 7.8% (n=14) of de novo ALL patients. In patients, whose biological material was available TP53 gene mutational status was determined in non-tumor cells (bone marrow and peripheral blood during remission, bone marrow samples after allogeneic hematopoietic stem cells transplantation and in tissue of non-hematopoietic origin) for discriminating germline mutations. The analysis included 5 patients (out of 14 with TP53 mutations), whose non-tumor biological material was available for research. Germline status was confirmed in 4 out of 5 B-cell ALL (n=3), T-cell ALL (n=1) investigated patients. Conclusion. Practical value of the research is the observation that the greater part of TP53 gene mutations in patients with Ph-negative B-cell ALL are germinal and associated with LFS.

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Le, Anh N., Timothy Delaney, Tara McWilliams, Maliha N. Tayeb, Caitlin Orr, Gregory Kelly, Ryan Hausler et al. « Increased risk for thyroid carcinoma in patients with Li-Fraumeni syndrome. » Journal of Clinical Oncology 42, n^o 16_suppl (1 juin 2024) : 10612. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.10612.

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10612 Background: Patients with Li-Fraumeni syndrome (LFS) are predisposed to a 90% lifetime risk of cancer, thus undergoing extensive cancer surveillance. While thyroid cancer is not a core LFS-associated malignancy, increased incidence of thyroid carcinoma has been reported within the LFS tumor spectrum. In the general population, thyroid cancer incidence has soared mainly via incidental detection. We investigated the rate of thyroid carcinoma in relation to p53 mutational process and increased screening. Methods: A retrospective chart review was conducted for clinico-pathological features for adult carriers of confirmed germline TP53 variants at three tertiary cancer centers. Standardized incidence ratio (SIR) was calculated using age, sex, and year-specific expected incidence rates of thyroid cancer from Surveillance, Epidemiology, and End Results (SEER) 1975 – 2020 data. Results: Among 600 patients from 400 families with LFS, 39 (6.5%) patients from 36 (9%) families developed thyroid carcinoma at an average age of 42 years (median = 40, ranged from 23 to 70 years of age). The majority of LFS patients with thyroid carcinoma were female (N=30, 77%). Thyroid carcinoma was the presenting cancer diagnosis in 17 (44%) patients. Over 70% of thyroid carcinoma diagnoses (N=31) were detected incidentally either via LFS cancer screening (N=12, 39%) or via an imaging study unrelated to LFS screening (N=10, 32%). All 39 thyroid carcinomas were of follicular cell origin (non-medullary), most were multifocal (67% of N=32), and 30% had nodal metastasis (N=10 of 33). Of 35 tumors with histologic data, papillary carcinoma (papillary, follicular, and tall cell subtypes) was most common (N=29, 83%), followed by follicular carcinoma (N=4, 11%) and oncocytic carcinoma (N=2, 6%). LFS patients most often underwent a total thyroidectomy (N=27, 69%) compared to a hemithyroidectomy (N=10, 26%) or hemithyroidectomy with completion surgery within three months (N=2, 5%). Intermediate to high risk of recurrence based on tumor characteristics was noted in 17 patients (44%), warranting consideration of radioactive iodine (RAI) therapy, including tall cell subtype (N=3), oncocytic or follicular histology, incomplete resection (N=2), extrathyroidal extension (N = 6), and greater than five positive lymph nodes (N=6). Five (29%) of these 17 patients received RAI. The SIR for thyroid carcinoma in LFS compared to SEER was 13 (95% CI 9.2-17.8, p<0.0001). The SIR was elevated for LFS patients diagnosed with thyroid carcinoma both prior to and after genetic testing (SIR 9.0, CI 5.3-14.2, p<0.0001 and SIR 20, CI 12.2- 30.9, p<0.0001, respectively). Conclusions: In this multi-institutional cohort, a 6-9% prevalence rate of thyroid carcinoma was observed in LFS patients and families, with >70% of the tumors identified incidentally. The rate of thyroid carcinoma in LFS is significantly elevated over the general population.

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Huffaker, Tyler, Stella Pak, Anum Asif et Prince Otchere. « Tricuspid mass-curious case of Li-Fraumeni syndrome : A case report ». World Journal of Clinical Cases 12, n^o 11 (16 avril 2024) : 1936–39. http://dx.doi.org/10.12998/wjcc.v12.i11.1936.

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BACKGROUND Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer-predisposing syndrome, which can manifest as a polymorphic spectrum of malignancies. LFS is associated with an early onset in life, with the majority of cases occurring prior to the age of 46. Notwithstanding the infrequency of primary cardiac tumors, it behooves clinicians to remain vigilant in considering the differential diagnosis of such tumors in LFS patients who present with a cardiac mass. This is due to the markedly elevated risk for malignancy in this particular population, far surpassing that of the general populace. CASE SUMMARY Herein, we present a case of a 30-year-old female with LFS who was found to have a tricuspid valve leaflet mass. CONCLUSION This case exemplifies valuable learning points in the diagnostic approach for this exceptionally rare patient population.

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Adlard, Julian, Cathy Burton et Philip Turton. « Increasing Evidence for the Association of Breast Implant-Associated Anaplastic Large Cell Lymphoma and Li Fraumeni Syndrome ». Case Reports in Genetics 2019 (16 juillet 2019) : 1–5. http://dx.doi.org/10.1155/2019/5647940.

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We report a case of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) occurring in a 53-year-old female with Li Fraumeni syndrome (LFS) with a prior history of breast cancer. We present the clinical features, investigation, and management of this patient and potential mechanisms that could explain the increasing association of BIA-ALCL and LFS.

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Quaglietta, Paula R., Ashby Kissoondoyal et David Malkin. « Abstract B019 : Characterization of the extracellular vesicle proteome in Li-Fraumeni Syndrome ». Cancer Research 84, n^o 17_Supplement (5 septembre 2024) : B019. http://dx.doi.org/10.1158/1538-7445.pediatric24-b019.

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Abstract Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline mutations in the TP53 tumor suppressor gene. People with LFS are burdened with an increased lifetime risk to develop a broad spectrum of malignancies, with a 21.2-fold higher relative risk for cancer development in children (0-19 years) versus non-LFS children. Mutations in TP53 (mutp53) abrogate normal tumor-suppressive functions, including DNA repair, cell cycle arrest, metabolism, and apoptosis. This causes cells to accumulate DNA damage, alters cellular behaviors inducing pro-proliferative effects, and alters the cellular secretome, including extracellular vesicles (EVs). In cancer, EVs are a key component of the tumor microenvironment and facilitate core cancer hallmark pathways to promote tumorigenesis and metastasis. LFS mutp53 carriers may be “primed” for cancer initiation, wherein pathogenic germline TP53 variants establish a pre-cancerous niche within the body. However, to our knowledge, no study has investigated the role of EVs in non-malignant mutp53 cells on the pre-cancerous state. We hypothesize that LFS cell-derived EVs contain unique cargo which play local and systemic roles to promote pre-cancer niche priming and tumorigenesis in LFS. EVs were isolated from cell culture conditioned media by differential ultracentrifugation from skin biopsy-derived dermal fibroblasts from LFS patients (R248Q, R273C, R273H mutations) and wildtype (WT) controls, each in triplicate. EVs were characterized using Western blotting, transmission electron microscopy, and nanoparticle tracking analysis. Liquid chromatography-tandem mass spectrometry identified and quantified EV protein cargo for differential expression analysis in R. Fibroblast-derived EV proteomes in both LFS and WT were distinguishable from their parent cell proteomes by principal component analysis. Within EV groups, we identified four significantly differentially expressed proteins (p<0.05; GAS6, P3H1, PSG4, VNN1), and key functions in LFS EVs compared to WT EVS. We further identified differences between EVs derived from specific LFS hotspot mutations, R248Q and R273C, including an additional four differentially expressed proteins (p<0.05; CDH2, KRT10, RPLP0, TPI1). Key functions and processes associated with inflammation, invasion, apoptosis, and immune cell interactions are being further explored through in vitro and in vivo methods. For the first time, we have demonstrated that basal differences exist in the EV protein cargo of LFS cells. Liquid biopsies provide a minimally invasive method to assess a patient’s cancer risk for a personalized medicine approach to LFS surveillance protocols. Further characterization of the LFS EV proteome may identify liquid biopsy biomarkers for early detection of cancer development and risk assessment for LFS individuals. These findings also suggest a novel approach to therapeutics in targeting LFS derived EVs. Investigating differentially expressed LFS EV proteins will identify potential targets unique to LFS individuals. Citation Format: Paula R. Quaglietta, Ashby Kissoondoyal, David Malkin. Characterization of the extracellular vesicle proteome in Li-Fraumeni Syndrome [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B019.

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Psarianos, Pamela, Nicholas Fischer et David Malkin. « Abstract 1124 : Prevention of radiation-induced malignancies in Li-Fraumeni syndrome ». Cancer Research 84, n^o 6_Supplement (22 mars 2024) : 1124. http://dx.doi.org/10.1158/1538-7445.am2024-1124.

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Abstract PURPOSE: Li-Fraumeni Syndrome (LFS) is a genetic disorder associated with a significant risk of early-onset cancer. This condition is driven by germline mutations in the TP53 gene which plays a primary role in the regulation of the radiation response. Aberrant TP53 function contributes to radiation vulnerability and a greater risk of secondary, radiation-induced malignancies (RIMs). As a result, therapeutic options for LFS patients are often limited to exclude radiotherapy (RT), which may otherwise be beneficial for the treatment of certain primary tumors. Data from our lab demonstrate an aberrant transcriptomic response to irradiation (IR) in mutant p53 patient skin fibroblasts compared to wildtype; however, it is unknown whether reprogramming this radiation response can decrease the risk of RIM in LFS. Metformin, a commonly prescribed anti-diabetic drug, is associated with lower cancer incidence and may decrease cancer-related mortality in murine LFS models. In addition to its potential anti-tumorigenicity, studies have shed light on the ability of metformin to prevent IR-induced damage in normal tissue; hence, we hypothesize that metformin can reprogram the radiation response to protect against radiation injury and delay the onset of RIM in LFS. METHODS: To establish a murine model of RIM in LFS, and to investigate whether metformin can delay tumor onset in this model, whole-body or localized IR were administered to mice harboring a hotspot Trp53R172H/+ mutation in the presence and absence of metformin. Serial MRI was conducted to monitor for tumor development. To understand the effect of metformin on the mutant p53 radiation response in vivo, a similar murine workflow was established and irradiated skin was collected longitudinally from untreated and metformin-treated cohorts for whole transcriptome sequencing. Sequencing data were functionally validated in a separate cohort of mice using flow cytometry. In parallel, we performed RNA sequencing on LFS patient fibroblasts to characterize the effect of metformin on the human radiation response. RESULTS: We demonstrate that IR decreases tumor latency in TP53R172H/+ mice, and that metformin significantly delays tumor onset within the radiation field. Moreover, transcriptomic data revealed that metformin upregulates apoptosis following IR in TP53R172H/+ mice. Flow cytometry analysis of the radiation response validated these findings, demonstrating that metformin promotes the apoptosis-driven clearance of damaged, potentially tumorigenic cells following IR. Transcriptomic data from patient cell lines will be presented. CONCLUSIONS: Overall, we show that metformin may delay RIM in LFS mice, and have begun to characterize the biology underpinning this reprogrammed response to IR. This study is the first to highlight metformin as a radioprotective agent in the context of germline mutant p53, with the potential to broaden RT treatment options for LFS patients. Citation Format: Pamela Psarianos, Nicholas Fischer, David Malkin. Prevention of radiation-induced malignancies in Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1124.

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Sidenna, Mariem, Reem Al Sulaiman, Tawfeg Ben-Omran, Salha Bujassoum et Amna Gameil. « Li-Fraumeni Syndrome : The Two Faces of a Coin in Myeloid Malignancies ». Blood 142, Supplement 1 (28 novembre 2023) : 5844. http://dx.doi.org/10.1182/blood-2023-188898.

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Background Li-Fraumeni Syndrome (LFS) is a rare, autosomal dominant genetic disorder caused by germline mutations in the TP53 tumor suppressor gene. It is characterized by a predisposition to a wide range of cancers, including hematological malignancies. Hematological malignancies account for approximately 3-4% of all LFS-related cancers of which are acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Myelodysplastic syndromes (MDS) and lymphomas. Method and Results We retrospectively analyzed our clinical data for patients with hematological malignances from the period of Jan 2016-Jan 2022 at the national center for cancer care and research (NCCCR), the only tertiary hematology center in the country. We report on two cases with Li Fraumeni syndrome with acute leukemia and their variable spectrum of the disease manifestations and prognosis. Case 1: 16 years old male known case of rheumatic heart disease presented with double malignancy; left mandible osteosarcoma and lymphoblastic leukemia/ lymphoma concurrently in 2020. For his Leukemia he received BFM*2009 protocol and after remission he underwent surgical resection and received radiotherapy for the osteosarcoma. Patient has family history of breast cancer in his maternal aunt and his paternal great aunt. Germline Genetic testing from buccal swab revealed a pathogenic variant in TP53 gene confirming Li Fraumeni syndrome which is most likely De novo as it was not detected in both parents and his 3 siblings. In 2022 patient presented with pancytopenia and therapy related AML/MDS with complex Karyotype. He was started on salvage therapy and was planned for allogenic stem cell transplant (SCT) from his HLA matched brother, however, unfortunately, patient didn't achieve complete remission thus could not receive the SCT and he passed away one year later in 2023. Case 2: 60-year-old female known case of hypertension who was diagnosed with right breast cancer in 2011 for which she underwent surgery, chemotherapy, and radiotherapy. A year later, patient was diagnosed with left upper lobe squamous cell lung carcinoma, and underwent left upper lobectomy, chemotherapy and radiotherapy. Patient was in remission for 6 years, until 2018 when she presented with pancytopenia and therapy related AML with complex monosomic Karyotype. Due to patient's age and comorbidities, she was unfit for intensive therapy, thus she received hypomethylation agent (Azacitidine) till disease progression and was referred to genetic counseling. Patient has a family history of unknown cancer in her paternal half-sister at the age of 77 and an unknown cancer in her paternal cousin. Genetic testing reveled a mosaic pathogenic variant in TP53 gene present in 17% of the 1137 next generation sequencing reads. Shortly later, patient passed away without confirmatory fibroblast testing. Conclusion: Genetic testing indications for Li-Fraumeni syndrome present challenges as patients with full mutationin TP53 often but not always present with the full spectrum of the disease, whereas patients with mosaic profilepresent with a later onset of the disease and might not be identified early. In both scenarios, patients can be miss-identified and exposed to radiotherapy thus testing criteria warrants further evaluation. Acute Leukemia in Li-Fraumeni syndrome is associated with poor prognosis and usually presents in the context of therapy related myeloid malignancies . Identification of patients with Li-Fraumeni syndrome early on is crucial to avoid exposures to radiotherapy whenever possible thus reducing the risk of subsequent malignancies and the tragic outcomes of the disease. There are unmet clinical needs in Li-Fraumeni syndrome diagnostic and therapeutic approaches which needs further attention.

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Song, Ran, Seeyoun Lee, Jai Hong Han, Jae Yeon Woo, Min Jung Lee, Han-Sung Kang, Sunhwa Park, Eun-Gyeong Lee, Sun Young Kong et So-Youn Jung. « Abstract 5215 : Clinical features of Li-Fraumeni syndrome in Korea ». Cancer Research 83, n^o 7_Supplement (4 avril 2023) : 5215. http://dx.doi.org/10.1158/1538-7445.am2023-5215.

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Abstract Purpose: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant hereditary disorder caused by a germline mutation in the TP53 gene. Because of the rarity of the disease, there were limited data on the types of the mutation, clinical features and treatment outcomes. The aim of this study is to evaluate the clinical characteristics and prognosis in Korean patients with germline TP53 gene mutation. Methods: Patients who underwent genetic counseling and confirmed with TP53 gene mutation in National Cancer Center in Korea between 2011 and 2022 were reviewed retrospectively. Data on family history with pedigree, types of mutation, clinical features and prognosis were collected. Results: Fourteen patients with LFS were included in the study. Missense mutations were shown in 13 cases and nonsense mutation in 1 case. The repeated mutations were p.Arg273His (n=2), p.Ala138Val (n=2) and pPro190Leu (n=2). A sister with breast cancer had the same mutation of p.Ala138Val. The median age at diagnosis of first tumor in 14 LFS patients was 32 (1-67) years. Seven patients (50%) had multiple primary cancers. Breast cancer was most frequently observed (n=9) and other types of tumor included sarcoma (n=5), thyroid cancer (n=3), pancreatic cancer (n=2), ovarian cancer (n=1), endometrial cancer (n=1), colon cancer (n=1), brain tumor (n=1), adrenocortical carcinoma (n=1), vaginal cancer (n=1), skin cancer (n=1) and leukemia (n=1). The median follow-up period was 51.5 (6-188) months. There were two cases of local recurrence and four cases of distant metastasis during the periods. Two patients died from leukemia and pancreatic cancer at three months and 23 months after diagnosis, respectively. Conclusion: As known in other countries, many Korean patients with LFS also had an early onset and multiple primary tumors. And patients showed various types of mutation, clinical features and prognostic outcomes. Further large-scale studies are required for proper screening and management in Korean patients with LFS. Grant: This study was supported by National cancer center, Korea, Grant no. 2110181 Citation Format: Ran Song, Seeyoun Lee, Jai Hong Han, Jae Yeon Woo, Min Jung Lee, Han-Sung Kang, Sunhwa Park, Eun-Gyeong Lee, Sun Young Kong, So-Youn Jung. Clinical features of Li-Fraumeni syndrome in Korea. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5215.

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Walcott, Farzana L., Christina M. Annunziata, Eduardo M. Sotomayor et Antonio Tito Fojo. « Effect of metformin chemoprevention on metabolomics profiles in Li-Fraumeni Syndrome (LFS). » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : 1556. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1556.

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1556 Background: LFS is a highly-penetrant, autosomal dominant, cancer predisposition disorder characterized by early onset cancer; germline mutations in TP53are present in 70% of LFS. We previously observed metformin inhibition on mitochondrial function in LFS patients. Metformin may reduce TCA cycle and glycolytic intermediates during cellular transformation, indicating inhibition of complex I of the mitochondria. To further explore this, we performed untargeted metabolomics profiling on stored serum of study participants. To our knowledge, there are no previous studies of metabolomics profiling in LFS patients treated with metformin. Methods: Adult LFS patients (≥18 years old) were enrolled for 20 weeks. Metformin was initiated at 500 mg per day and increased in 500 mg dose increments every two weeks to a maintenance dose of 2000 mg of metformin. Patients were taken off metformin for the last six weeks of the study (week 20). Global biochemical profiles were determined in human serum samples collected in 21 patients, each providing one sample at baseline, week 14 (on 2000 mg metformin) and week 20 (off metformin). Metabolomics analyses were performed by Metabolon, Inc. Results: Treatment with metformin induced a strong metabolic signature of increased fatty acid beta-oxidation in LFS patients. Acylcarnitines, long chain fatty acids, and 3-hydroxy fatty acids were significantly elevated following metformin treatment. TCA cycle intermediates, aconitate, malate, and fumarate were also increased as were levels of ketone body 3-hydroxybutyrate (BHBA)indicating robust β-oxidation, presumably to support increased energy production via the TCA cycle. Clearance of metformin results in normalization of levels to comparable baseline values, indicating a causal role of metformin in these changes. Conclusions: Global metabolomics profiling suggests an increase in TCA cycle intermediates and a strong signature of fatty acid oxidation with metformin treatment in LFS, suggesting metformin effect on the mitochondria and TCA cycle is more dynamic than previously shown. LFS patients may have distinct metabolic profiles which may be altered by treatment with metformin. Funding: ASCO Young Investigator’s Award 2016. Clinical trial information: NCT01981525.

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Cenci, Giulia, et Valerio Pace. « Orthopedic manifestations of Li-Fraumeni syndrome : Prevention and treatment of a polymorphic spectrum of malignancies ». World Journal of Clinical Cases 12, n^o 26 (16 septembre 2024) : 5839–44. http://dx.doi.org/10.12998/wjcc.v12.i26.5839.

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Li-Fraumeni syndrome (LFS) is a rare hereditary cancer predisposition syndrome characterized by a heightened risk of developing various malignancies at an early age. Emerging evidence suggests a correlation between LFS and orthopedic manifestations, underscoring the importance of orthopedic screening in individuals with this syndrome. Pediatric cancer is rare. It is estimated that more than 10%-15% of tumors are secondary to a pathogenic variant in a cancer predisposition gene. More than 100 cancer predisposition genes and their association with syndromes or isolated tumors have been identified. LFS is one of those who have been most widely described. Patients with this syndrome present a high risk of developing one or more tumors. Its knowledge enables the establishment of a follow-up protocol for the patient and affected family members, facilitating early detection of new tumors and reducing tumor and treatment-related morbidity and mortality. The primary objective of this invited editorial article is to provide a thorough review of the existing knowledge of LFS and its polymorphic spectrum of related malignancies, with a focus on aspects directly linked to orthopedic manifestations. Another objective is to offer an update on the most modern prevention, treatment and follow up guidelines that could be useful for the physicians dealing with this cohort of patients.

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Nehoray, Bita, Alison Schwartz, Sophie Hyman, Samantha Stokes, Aleck Cervantes, Christopher Amos, Stephen B. Gruber et Judy Ellen Garber. « Questioning a Li-Fraumeni Syndrome diagnosis : Characterization of a commonly observed germline TP53 variant, p.Arg156His. » Journal of Clinical Oncology 40, n^o 16_suppl (1 juin 2022) : 10612. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.10612.

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10612 Background: Germline pathogenic variants (PV) in the TP53 gene are associated with Li-Fraumeni syndrome (LFS). Increased use of multi-gene panel testing has identified TP53 variants suspected to have reduced penetrance, a departure from the significantly increased cancer risks expected with LFS, posing challenges in variant classification and clinical management. TP53 c.467G>A (p.Arg156His), R156H, is a variant with over 250 observations across multiple laboratories with prior discordant classification. R156H was recently downgraded by laboratories from likely pathogenic (VLP) to variant of uncertain significance (VUS). Characterization of R156H to clarify clinical significance has the potential to impact care for many. Methods: R156H carriers were identified through the Li-Fraumeni & TP53: Understanding & Progress (LiFT UP) study ( https://liftupstudy.org ) from 2019-2022. Clinical data were collected and reviewed for phenotypic characterization and to determine whether LFS Classic and/or Chompret criteria were met, and to assign Li-Fraumeni spectrum classification (Kratz et al.). Results: Proband/family characteristics are in the Table. Twenty R156H carriers were identified in 11 families. Seventeen carriers had a personal history of cancer; 8 had a LFS core cancer. All core cancers were breast except for an astrocytoma and a pediatric sarcoma. Two breast cancer cases also carried a BRCA2 PV. The average age at first cancer diagnosis was 40.5 years (range 6-71). No families met Classic LFS criteria. One proband met Chompret criteria due to breast cancer <31 years (who also carried a BRCA2 PV). Ten families were classified as attenuated LFS per Kratz et al. Conclusions: Most families in our case series did not meet LFS criteria, raising the question of appropriate clinical management and the willingness to de-escalate LFS surveillance. Our series supports the downgrade to VUS, but the presence of a few non-breast LFS core cancers warrants work to determine if R156H is a reduced penetrance PV. Recruitment of these families is ongoing through the LiFT UP study to perform segregation analyses and cancer risk estimations. This work may guide evaluation of other variants presenting similar challenges. [Table: see text]

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Bharathi, Sainath Prasanna, et Velmurugan Ramaiyan. « Complexity in interpreting cardiac valve-associated thrombus from tumors in Li-Fraumeni syndrome ». World Journal of Clinical Cases 12, n^o 31 (6 novembre 2024) : 6431–35. http://dx.doi.org/10.12998/wjcc.v12.i31.6431.

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Li-Fraumeni syndrome (LFS) is a well-defined autosomal dominant predisposition syndrome due to TP53 germline mutation that causes many cancer malignancies. This early-onset syndrome poses a state of widespread malignancy. Such an inherited condition possessing defective p53, guardian of the genome, in the germline has the potential to cause multiple cancers by predominantly affecting mesenchyme (connective tissues, blood cells), breast, brain, and adrenal cortex organs. The tumors initially identified in LFS can eventually propagate to cause secondary malignancies. LFS contributes to multiple cancers in individuals with defective p53 inheritance. When suspected to possess any mass, patients with other co-morbidities, in particular those with certain cardiovascular conditions, undergo screening using high-throughput techniques like transthoracic and transesophageal echocardiography or cardiothoracic magnetic resonance imaging to locate and interpret the size of the mass. In LFS cases, it is certain to presume these masses as cancers and plan their management employing invasive surgeries after performing all efficient diagnostic tools. There are only poor predictions to rule out the chances of any other pathology. This criterion emphasizes the necessity to speculate alternative precision diagnostic methods to affirm such new growth or masses encountered in LFS cases. Moreover, it has all the possibilities to ultimately influence surgical procedures that may be invasive or complicate operative prognosis. Hence, it is essential to strategize an ideal protocol to diagnose any new unexplored mass in the LFS community. In this editorial, we discuss the importance of diagnostic approaches on naïve pristine masses in LFS.

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Raymond, Victoria M., Tobias Else, Jessica N. Everett, Jessica M. Long, Stephen B. Gruber et Gary D. Hammer. « Prevalence of Germline TP53 Mutations in a Prospective Series of Unselected Patients with Adrenocortical Carcinoma ». Journal of Clinical Endocrinology & ; Metabolism 98, n^o 1 (1 janvier 2013) : E119—E125. http://dx.doi.org/10.1210/jc.2012-2198.

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Abstract Purpose: Adrenocortical carcinoma (ACC) is a hallmark cancer in families with Li Fraumeni syndrome (LFS) caused by mutations in the TP53 gene. The prevalence of germline TP53 mutations in children diagnosed with ACC ranges from 50–97%. Although existing criteria advocate for TP53 testing in all patients with ACC regardless of age at diagnosis, the overall prevalence of germline mutations in patients diagnosed with ACC has not been well studied. Patients and Methods: A total of 114 patients with confirmed ACC evaluated in the University of Michigan Endocrine Oncology Clinic were prospectively offered genetic counseling and TP53 genetic testing, regardless of age at diagnosis or family history. Ninety-four of the 114 patients met with a genetic counselor (82.5%), with 53 of 94 (56.4%) completing TP53 testing; 9.6% (nine of 94) declined testing. The remainder (32 of 94; 34%) expressed interest in testing but did not pursue it for various reasons. Results: Four of 53 patients in this prospective, unselected series were found to have a TP53 mutation (7.5%). The prevalence of mutations in those diagnosed over age 18 was 5.8% (three of 52). There were insufficient data to estimate the prevalence in those diagnosed under age 18. None of these patients met clinical diagnostic criteria for classic LFS. Three of the families met criteria for Li Fraumeni-like syndrome; one patient met no existing clinical criteria for LFS or Li Fraumeni-like syndrome. Three of the four patients with mutations were diagnosed with ACC after age 45. Conclusions: Genetic counseling and germline testing for TP53 should be offered to all patients with ACC. Restriction on age at diagnosis or strength of the family history would fail to identify mutation carriers.

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Neofytou, Kyriakos, Simone Famularo et Aamir Z. Khan. « PEComa in a Young Patient with Known Li-Fraumeni Syndrome ». Case Reports in Medicine 2015 (2015) : 1–4. http://dx.doi.org/10.1155/2015/906981.

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Perivascular epithelioid cells neoplasms (PEComas) constitute a family of rare tumours which have been reported virtually in all anatomic sites. The histological clarification of the malignant potential of these tumours is still problematic despite the proposed risk stratification systems. Li-Fraumeni syndrome (LFS) is caused by a germline mutation in the TP53 tumour suppressor gene. It is a rare but well-characterized cancer predisposition syndrome leading to the development of a variety of different tumour types. To the best of our knowledge, an association between this syndrome and PEComas has not been previously documented. A 24-year-old lady with known LFS presented with two uncertain-in-nature lesions, one within the right part of the liver and one within the upper pole of the right kidney. The patient underwent an uncomplicated open simultaneous right partial nephrectomy and resection of segment 7 of the liver. The morphological and immunohistochemical features of both lesions were of epithelioid angiomyolipoma (PEComa). Although the obvious scenario was that the liver lesion was a metastasis from the renal lesion, the assessment of their malignant potential according to the existing risk stratification systems was rather in favour of two synchronous primary PEComas, pointing out that the histological assessment of malignant potential of PEComas is still problematic.

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Al-Haggar, Mohammad S., et Zahraa A. Abdelmoneim. « Tricuspid mass-curious case of Li-Fraumeni syndrome : A letter to the editor ». World Journal of Clinical Cases 12, n^o 33 (26 novembre 2024) : 6644–46. http://dx.doi.org/10.12998/wjcc.v12.i33.6644.

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We focus specifically on the rare occurrence of cardiac thrombi in Li-Fraumeni syndrome (LFS). LFS is a hereditary risk to a diverse range of specific, uncommon, malignancies. Children and young adults have a heightened susceptibility to many malignancies, particularly soft-tissue and bone tumors, breast malignancies, central nervous system malignancies, adrenocortical carcinoma, and blood cancers. Additionally, LFS patients may experience other cancer types such as gastrointestinal, lung, kidney, thyroid, and skin cancers, along with those affecting gonadal organs (ovaries, testicles, and prostate). An accurate diagnosis of LFS is crucial to enable affected families to access appropriate genetic counseling and undergo surveillance for early cancer detection.

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Kolodziejczak, Anna, Lea Guerrini-Rousseau, Julien Masliah Planchon, Jonas Ecker, Florian Selt, Martin Mynarek, Denise Obrecht et al. « MEDB-14. Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome ». Neuro-Oncology 24, Supplement_1 (1 juin 2022) : i107. http://dx.doi.org/10.1093/neuonc/noac079.389.

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Abstract PURPOSE: The prognosis for SHH-medulloblastoma (MB) patients with Li-Fraumeni syndrome (LFS) is poor. Due to lack of comprehensive data for these patients, it is challenging to establish effective therapeutic recommendations. We here describe the largest retrospective cohort of pediatric LFS SHH-MB patients to date and their clinical outcomes. PATIENTS AND METHODS: N=31 patients with LFS SHH-MB were included in this retrospective multicenter study. TP53 variant type, clinical parameters including treatment modalities, event-free survival (EFS) and overall survival (OS), as well as recurrence patterns and incidence of secondary neoplasms, were evaluated. RESULTS: All LFS-MBs were classified as SHH subgroup, in 30/31 cases based on DNA methylation analysis. The majority of constitutional TP53 variants (72%) represented missense variants, and all except two truncating variants were located within the DNA-binding domain. 54% were large cell anaplastic, 69% gross totally resected and 81% had M0 status. The 2-(y)ear and 5-(y)ear EFS were 26% and 8,8%, respectively, and 2y- and 5y-OS 40% and 12%. Patients who received post-operative radiotherapy (RT) followed by chemotherapy (CT) showed significantly better outcomes (2y-EFS:43%) compared to patients who received CT before RT (30%) (p<0.05). The 2y-EFS and 2y-OS were similar when treated with protocols including high-dose chemotherapy (EFS:22%, OS:44%) compared to patients treated with maintenance-type chemotherapy (EFS:31%, OS:45%). Recurrence occurred in 73.3% of cases independent of resection or M-status, typically within the radiation field (75% of RT-treated patients). Secondary malignancies developed in 12.5% and were cause of death in all affected patients. CONCLUSIONS: Patients with LFS-MBs have a dismal prognosis. This retrospective study suggests that upfront RT may increase EFS, while intensive therapeutic approaches including high-dose chemotherapy did not translate into increased survival of this patient group. To improve outcomes of LFS-MB patients, prospective collection of clinical data and development of treatment guidelines are required.

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Kissoondoyal, Ashby, et David Malkin. « Abstract A009 Single cell transcriptomic signature of Li-Fraumeni Syndrome soft tissue sarcomas ». Cancer Research 84, n^o 17_Supplement (5 septembre 2024) : A009. http://dx.doi.org/10.1158/1538-7445.pediatric24-a009.

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Abstract Li-Fraumeni Syndrome (LFS) is a genetic predisposition disorder associated with pathogenic germline Tp53 mutations. A subset of LFS-associated neoplasms occurs at an increased risk within the first 5 years of life, with the most common being soft tissue sarcomas (STS). Histological characterization of STS is one of the primary approaches to guiding treatment. However, the heterogeneity of STS has necessitated a further understanding of the molecular etiology of these tumors. Examining sarcomas using a single-cell transcriptomic approach has shown unique subsets of cells with dysregulations in cell fate and differentiation. Within LFS-associated tumors, including LFS-STS a major event in tumorigenesis is the copy-neutral loss of heterozygosity (LOH). LOH was determined to occur much earlier than cancer onset in LFS, suggesting a dormancy period from the LOH until tumorigenesis; cancer-defining events in LFS are likely occurring prenatally. During embryogenesis, Tp53 is involved in differentiation and pluripotency regulation, as well as cell cycle control and apoptosis. Here we hypothesize that the emergence of STS in LFS mice is associated with distinct disturbances in the cell fate and differentiation pathways. Specifically, there will be deficits in cell fate determination and the organization of cells across multiple cell types in LFS-Sarcomas. Single-cell RNAseq was performed on spontaneous tumors and healthy matched muscle tissue from male and female C57BL/6J Trp53R172H/WT mice. Cell types were determined based on differential gene expression between clusters defined by principal component analysis. Despite tumor heterogeneity between mice, there were consistent disruptions of developmental pathways among tumor cells. Moreover, when comparing matched cell types across tumor and healthy muscle tissue we observed dysregulation of pathways promoting tumorigenesis, and cell fate determination in cells originating from tumor tissue. For the first time to our knowledge, this study examines the single-cell transcriptome of LFS-STS. Current literature has speculated on the presence of an early precancer state of LFS-associated tumors. This study will provide evidence to determine whether this precancer state can be determined in tumor samples, and identify elements that constitute this state. Moreover, we will determine changes in supporting non-tumor cells and whether they also exhibit dysregulations in cell state and differentiation. Together these findings will hopefully contribute to improvements in molecular subtyping across STS, and particularly within LFS individuals. Citation Format: Ashby Kissoondoyal, David Malkin. Single cell transcriptomic signature of Li-Fraumeni Syndrome soft tissue sarcomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A009.

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Zaheed, Milita, Christine E. Napier, Elisa J. Cops, Nick Ferris, Kate Moodie, Brad Milner, Daniel Moses et al. « Long-term clinical and psychosocial outcomes of surveillance in Li Fraumeni syndrome. » Journal of Clinical Oncology 41, n^o 16_suppl (1 juin 2023) : 10578. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.10578.

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10578 Background: Li Fraumeni Syndrome (LFS) is a high penetrance multi-organ cancer predisposition syndrome, associated with a significant lifetime risk of developing cancer. The Surveillance study in Multi-Organ Cancer prone syndromes (SMOC+) is investigating the utility of annual surveillance, with inclusion of whole-body magnetic resonance imaging (WBMRI), for hereditary cancer syndromes without well-established risk management strategies. Here we report the long-term clinical and psychosocial outcome of surveillance in participants with LFS. Methods: Multimodality surveillance in this multi-centre, prospective, longitudinal, observational study for adult participants with LFS included annual clinic review and examination, WBMRI, breast MRI (MRIB), full blood count, prostate specific antigen; 2-5 yearly gastro-intestinal endoscopy and faecal occult blood test in intervening years. Quantitative psychometric evaluations were requested at regular intervals each year using Hospital Anxiety and Depression Scale (HADS), the Impact of Events scale anchored to cancer (IES-C), and the Impact of Events scale MRI (IES-MRI). Results: From July 2013 to December 2021, 132 (67% female) participants were enrolled at a median age of 36 (range 18-69 )years. There were 116 prior diagnoses of neoplasms among 68 (52%) participants, including 27 (20%) with multiple primaries. At a median follow up of 4 years, 46 new primary malignancies were diagnosed in 30 (23%) individuals, with median age at diagnosis of 43 (range 24-71 years). Four (3%) individuals developed recurrence of a prior malignancy. The malignancies were detected as a result of WBMRI (27), MRIB (7), gastroscopy (1), colonoscopy (1) and clinical review and examination (17). The most frequent new primaries were leiomyosarcoma and breast cancer (Table). Overall, 22 (17%) are not currently participating due to cancer related death (10), active cancer (6) or other life events (6). At 4 years after enrollment, 94, 80 and 50 participants completed at least one HADS (463 unique observations), IES-C (362 unique observations), and IES-MRI (268 unique observations) questionnaire, respectively. Controlling for demographic and cancer history variables, there was no evidence of changes in overall anxiety or depression (p=0.2), nor in degrees of distress associated with cancer (p=0.06) or WBMRI (p=0.6) over time. Conclusions: In LFS, annual surveillance with WBMRI is feasible and well tolerated, with no difference in distress experienced in the longer term. Over 80% of participants continue to engage with surveillance. The majority of cancer-affected individuals were able to resume surveillance after management of early disease. [Table: see text]

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Psarianos, Pamela, Nicholas Fischer, Camilla Giovino, Noel Ong et David Malkin. « Abstract 849 : Characterization and prevention of radiation-induced malignancies in Li-Fraumeni Syndrome ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 849. http://dx.doi.org/10.1158/1538-7445.am2022-849.

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Abstract PURPOSE: Li-Fraumeni Syndrome (LFS) is a genetic disorder associated with a significant risk of early-onset cancer. This condition is largely driven by germline mutations in the TP53 tumor suppressor, which has a broad spectrum of functions including the transcriptional regulation of radiation response. Termed the guardian of the genome, TP53 serves as a critical checkpoint which coordinates DNA repair, cell cycle progression and apoptosis following DNA damage, ultimately controlling the fate of the cell. Aberrant or deficient TP53 function, such as occurs in LFS, contributes to radiation vulnerability. As a result, there is particular caution in the use of radiotherapy to treat primary LFS tumors, in order to prevent the formation of secondary, radiation-induced malignancies. To this end, therapeutic options for LFS are often limited to surgery and chemotherapy, posing substantial constraints for the treatment of patients who may otherwise benefit from primary tumor radiation. Metformin, a commonly prescribed anti-diabetic drug, is associated with lower cancer incidence in populations worldwide. Recent studies have shed light on the potential utility of metformin as a pharmacopreventive agent for primary tumors in LFS; hence, we hypothesize that the utility of metformin can be extended to the prevention of secondary malignancies following radiotherapy in LFS. METHODS/RESULTS: To explore the chemopreventive potential of metformin in LFS, we completed tumor challenges using a p53R172H/+ LFS mouse model. Mice treated prophylactically with metformin showed slower xenograft tumor growth compared to vehicle-treated mice. Ongoing work in our lab aims to characterize the effects of metformin on tumor growth following the administration of localized ionizing radiation (IR) to LFS mice. Briefly, these mice are treated with either vehicle or metformin, and IR is administered to the left hindlimbs to induce tumor formation. The timing and rates of tumor growth are monitored using magnetic resonance imaging. At endpoint, excised tumors are subjected to global profiling via RNA sequencing, proteomic analysis, and single-cell sequencing of discrete cell populations to characterize the effects of metformin on the development of radiation-induced malignancies. Results of these studies will be presented. SIGNIFICANCE: Overall, this work will advance our understanding of the chemopreventive effects of metformin, with the potential to broaden the treatment options available to LFS patients. Citation Format: Pamela Psarianos, Nicholas Fischer, Camilla Giovino, Noel Ong, David Malkin. Characterization and prevention of radiation-induced malignancies in Li-Fraumeni Syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 849.

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Ong, Noel WY, Camilla M. Giovino, Nicholas W. Fischer, Pamela Psarianos et David Malkin. « Abstract A013 Exploring the role of microbiota in cancer development in Li-Fraumeni Syndrome ». Cancer Research 84, n^o 17_Supplement (5 septembre 2024) : A013. http://dx.doi.org/10.1158/1538-7445.pediatric24-a013.

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Abstract Li-Fraumeni Syndrome (LFS) is an inherited cancer predisposition syndrome caused by pathogenic TP53 germline variants and associated with an elevated risk to develop a wide spectrum of malignancies. LFS patients are prone to develop multiple cancers throughout their lifetime, with significantly earlier onset compared to the general population. Currently, there is no cure for LFS; the primary approach to managing LFS is early tumor surveillance to detect tumors in their early state while they are relatively easier to treat. Microbes have been increasingly recognized for their roles in cancer development and progression. Microbes can contribute to cancer risk via the production of DNA-damaging toxins and carcinogenic metabolites which can induce cancer-promoting inflammation. However, the interactions between the microbiome and mutant p53 in Li-Fraumeni Syndrome have not been fully explored. To investigate the contribution of microbes to cancer development in LFS, we depleted the microbiota of Trp53R172H/WT mice (LFS mice; TP53-R175H human homolog) using a wide spectrum of antibiotics. Following 4 days of antibiotic treatment, LFS mice were subcutaneously injected with the MC38 colon adenocarcinoma cell line. Antibiotic treatment was continued until the endpoint of the study. We observed that the antibiotic-treated LFS mice exhibited smaller tumor mass compared to untreated LFS mice, while no antibiotic-associated changes were observed in wildtype littermates. This finding might suggest that the gut microbiome contributes to cancer development in LFS mice. To interrogate whether the gut microbiome of LFS mice promotes tumor development, we conducted faecal filtrate transplant (FFT) from LFS mice—which transfers the microbial metabolites from the faeces in the absence of the microbes themselves—into the wildtype littermates via oral gavage. We observed that the FFT transferred from LFS mice to wildtype littermates was associated with increased tumor growth, which may further support the notion that the gut microbiome in LFS mice promotes tumorigenesis. Microbes can influence tumor development via many different mechanisms, one of which is by inducing cancer-promoting inflammation. The NF-κB pathway plays a central role in inflammation, and it is a crucial component of the immune response to microbial infection. NF-κB signalling is also linked to cancer initiation and progression through the promotion of chronic inflammation. Studies have demonstrated that mutant p53 upregulates the NF-κB pathway in vitro, and is activated in response to microbial infection. Here, we show that NF-κB activity was upregulated in the intestines of LFS mice. Upon FFT-treatment in wildtype p53 mice, the NF-κB activity in the intestine was upregulated. This finding suggests that the gut microbiome in LFS mice promotes inflammation in the intestine, which may further contribute to cancer-causing systemic inflammation. In summary, this work provides insight into the influence of the microbiome on cancer susceptibility in LFS. Citation Format: Noel WY Ong, Camilla M. Giovino, Nicholas W. Fischer, Pamela Psarianos, David Malkin. Exploring the role of microbiota in cancer development in Li-Fraumeni Syndrome [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A013.

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Kolodziejczak, Anna, Lea Guerrini-Rousseau, Julien Masliah Planchon, Martin Mynarek, Martin Sill, Robert Autry, Eric Zhao et al. « MDB-15. CLINICAL CHARACTERISTICS AND OUTCOME OF CHILDHOOD LI-FRAUMENI SYNDROME MEDULLOBLASTOMA PATIENTS ». Neuro-Oncology 25, Supplement_1 (1 juin 2023) : i64—i65. http://dx.doi.org/10.1093/neuonc/noad073.248.

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Abstract Patients with Li-Fraumeni syndrome (LFS) who develop medulloblastoma (MB) have a very poor prognosis. The development of novel therapeutic strategies is challenged by the lack of clinical data for this patient group. We here present clinical and molecular data on a retrospective cohort of pediatric patients with LFS-associated MB. This is an international, retrospective, multicenter cohort study. Patients with LFS-associated MB under 21 years and class 5 (pathogenic) or class 4 (likely pathogenic) constitutional TP53 variants were included. We evaluated TP53 mutation status (constitutional and somatic), DNA methylation subgroup, treatment modalities, event-free (EFS) and overall survival (OS), patterns of recurrence, as well as occurrence of secondary neoplasms. Forty-seven individuals with LFS-associated MB were included. MBs were classified mainly as Sonic Hedgehog (SHH) group (87%). TP53 variants were classified as class 5 (70%) and class 4 (30%). The majority (74%) of TP53 variants represented missense variants. The 2-year (y-) EFS and -OS were 33% and 53%, respectively. A significantly better outcome was seen in patients who received post-operative radiotherapy (RT) (2y-EFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-EFS: 24%, 2y-OS: 48%) compared with patients who received no RT (2y-EFS: n.a., 2y-OS: 25%). No significantly different outcomes were seen between patients treated either according to protocols including high-intensity chemotherapy or receiving only maintenance-type chemotherapy (2y-EFS: 42% and 31%, 2y-OS: 68% and 53%, respectively). Patients with LFS-associated MB have a dismal prognosis. Use of RT in LFS-associated MB significantly increased survival rates in the presented cohort, but choice of chemotherapy regimen did not influence their clinical outcome. To improve the outcome of patients with LFS-associated MB, prospective collection of clinical data and development of novel treatments are required.

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Michaeli, Orli, Uri Tabori, Joshua David Schiffman, Anne Naumer, Wendy Kohlmann, D. Gareth Evans, Claire Forde et al. « Gliomas in the context of Li-Fraumeni syndrome : An international cohort. » Journal of Clinical Oncology 37, n^o 15_suppl (20 mai 2019) : 1517. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.1517.

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1517 Background: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline mutation in the TP53 tumor suppressor gene. As a result of increased awareness and surveillance imaging, more asymptomatic low-grade brain lesions are being identified, raising important questions regarding the management of those patients. Sporadic low-grade gliomas (LGG) in the pediatric age rarely transform to malignant lesions, whereas the prognosis of high-grade gliomas (HGG) is grim in all age groups. Although HGG is a hallmark of LFS, little is known of the natural history of these lesions in this syndrome. Methods: For this multi-institutional retrospective study, anonymized clinicopathologic data from TP53 mutation carriers with gliomas were collected and analysed. Results: Our cohort included 61 patients, of whom 71% (n = 45) were children or young adults (age < 25 years). 39% of patients with known family history of cancer had a close relative with a brain tumor. Of 31 patients with low grade lesions at presentation, 83% (n = 26) were identified through surveillance. Five-year progression free survival (PFS) for these patients was 48%, though two patients progressed later. Furthermore, at 5 years 25% of these patients had biopsy proven malignant transformation to HGG. This “transformation free survival” rate did not plateau, as at 7 years 56% of patients transformed. When considering death from a brain tumor, the 5- and 10- year overall survival (OS) for the LGG group was 100% and 83%, respectively. Additional 3 patients succumbed to other LFS related malignancies. For the HGG group, consisting of 30 patients, the 5 year OS was 35% (median follow-up 19.5 months), comparing favorably with the sporadic HGG population as reported in the literature. Almost all of these patients presented with clinical symptoms. Notably, 12 (40%) of them had a prior malignancy. Conclusions: Our analysis suggests that the risk of transformation of LGG in the setting of LFS is high and warrants ongoing surveillance. Interestingly, there are a considerable number of long- term survivors in our HGG group, although the median follow up is still short. Further study to examine potential genotype- phenotype correlations in germline TP53 mutation carriers will inform strategies to identify those patients at highest risk of glioma progression.

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Bachinski, Linda L., Shodimu-Emmanuel Olufemi, Xiaojun Zhou, Chih-Chieh Wu, Linwah Yip, Sanjay Shete, Guillermina Lozano, Christopher I. Amos, Louise C. Strong et Ralf Krahe. « Genetic Mapping of a Third Li-Fraumeni Syndrome Predisposition Locus to Human Chromosome 1q23 ». Cancer Research 65, n^o 2 (15 janvier 2005) : 427–31. http://dx.doi.org/10.1158/0008-5472.427.65.2.

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Abstract Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome. Most cases (∼70%) identified and characterized to date are associated with dominantly inherited germ line mutations in the tumor suppressor gene TP53 (p53) in chromosome 17p13.1. In a subset of non-p53 patients with LFS, CHEK2 in chromosome 22q11 has been identified as another predisposing locus. Studying a series of non-p53 LFS kindred, we have shown that there is additional genetic heterogeneity in LFS kindred with inherited predisposition at loci other than p53 or CHEK2. Using a genome-wide scan for linkage with complementing parametric and nonparametric analysis methods, we identified linkage to a region of approximately 4 cM in chromosome 1q23, a genomic region not previously implicated in this disease. Identification ofa third predisposing gene and its underlying mutation(s) should provide insight into other genetic events that predispose to the genesis of the diverse tumor types associated with LFS and its variants.

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Yi, Andy, Jongwon Yun, Jian Lee et KyuBin Park. « Li-Fraumeni Syndrome in Breast Cancer : Development of Theranostic Probes on Variation of P53 ». Technium BioChemMed 10 (14 octobre 2024) : 1–10. http://dx.doi.org/10.47577/biochemmed.v10i.11797.

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Li-Fraumeni Syndrome (LFS) is a hereditary condition characterized by a high predisposition to various cancers due to mutations in the p53 protein. Effectively targeting and treating this syndrome requires early detection and personalized treatment according to one’s specific nucleotide sequence. With the use of various forms of theranostics, LFS can be treated, increasing life expectancy; however, there is no absolute cure that could immediately end this syndrome. This paper delves into three different theranostic approaches: Gendicine (rAd-p53), Phesgo, and gold nanoshell poly(D, L-lactic-co-glycolic acid) nanoparticles (PLGA NPs). While each approach has limitations, PLGA nanoparticles exhibit advantages that outweigh their drawbacks, making it an attractive solution. This proposal will describe improvements to PLGA nanoparticles, which are a promising area of research for the development of new LFS treatments.

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Shrebati, Adnan, Pierre Loap et Youlia Kirova. « Adjuvant Radiotherapy and Breast Cancer in Patients with Li-Fraumeni Syndrome : A Critical Review ». Cancers 17, n^o 7 (1 avril 2025) : 1206. https://doi.org/10.3390/cancers17071206.

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Background/Objectives: Li-Fraumeni syndrome (LFS) is a disease caused by a germline mutation of the tp53 gene that predisposes the individual to various malignancies, including breast cancer. Its impact on treatment modalities in oncology remains poorly studied. In this critical review, we aimed to retrieve and analyze available data concerning adjuvant radiotherapy in early breast cancer for LFS patients, as well as the current guidelines. Methods: We reviewed articles with LFS patient cohorts that reported secondary malignancy rates after breast adjuvant radiotherapy. Rates of recurrence, when available, were also included. Furthermore, we discussed contemporary radiobiological evidence and guidelines on the subject. Results: Six retrospective studies were reviewed. Five reported much higher rates of secondary malignancies compared to the general population. Additionally, there was no clear trend toward increased locoregional control after adjuvant radiotherapy. Radiobiological data suggest increased radioresistance and radiosensitivity within p53-mutated cells. Guidelines recommend avoiding radiotherapy in LFS patients when possible. Conclusions: Currently, there is no standard treatment or cure for LFS or a germline variant of the TP53 gene. With few exceptions, cancers in people with LFS are treated the same way as cancers in other patients, but research continues into the best way to manage cancers involved in LFS.

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Poli, Tito, Francesco Laganà, Luigi Caradonna, Roberta Gobbi, Domenico Corradi et Enrico Sesenna. « Primary Orbital Liposarcoma in Li-Fraumeni Cancer Family Syndrome : A Case Report ». Tumori Journal 91, n^o 1 (janvier 2005) : 96–100. http://dx.doi.org/10.1177/030089160509100121.

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Aims and background The aim of this study was to describe a case of primary orbital liposarcoma in Li-Fraumeni syndrome. Methods and study design In July 1998 a 20-year-old woman with a histological diagnosis of orbital myxoid liposarcoma underwent surgical treatment in our department. Since the patient's family pedigree met the clinical criteria for the diagnosis of LFS, molecular analysis was performed, which resulted in a molecular profile consistent with Li-Fraumeni syndrome. Results The patient underwent orbital exenteration extended to the upper eyelid; surgical reconstructive steps were performed to permit placement of an orbital prosthesis. Two years after primary surgery the patient underwent a quadrantectomy with lymphadenectomy of the right axilla because of the presence of a nodule of 1.5 cm in diameter in the upper-lateral quadrant of the right breast. One year after the last surgery, the patient is disease free. Conclusion The diagnosis of an orbital malignancy in a young patient with a family history of cancer should suggest the presence of an underlying genetic disorder like LFS; with molecular analysis we can now determine the genetic disorder and the exact location of the mutation, and also obtain important prognostic data using specific cellular markers. More prognostic information increases the chances of adequate personalized treatment.

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Ong, Noel Wei, Camilla Maria Giovino, Nicholas William Fischer, Pamela Psarianos et David Malkin. « Abstract 3047 : Investigating the interaction between the microbiome and mutant p53 in Li-Fraumeni Syndrome ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 3047. http://dx.doi.org/10.1158/1538-7445.am2022-3047.

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Abstract Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome in which affected individuals are prone to developing a wide spectrum of malignancies. LFS is caused by germline mutations in the TP53 tumour suppressor gene. LFS patients develop cancer significantly earlier than the general population and may experience multiple malignancies in their lifetime. Studies have indicated that environmental influences like radiation exposure and tobacco smoke may further increase cancer risk in LFS patients. Currently, there is no cure for LFS, and screening for early tumour detection is the standard of care for LFS patients. Recently, microbes have been found to be involved in cancer development, progression, and treatment responsiveness. Moreover, microbes have anti-tumourigenic properties that can be harnessed for therapeutic intervention. The interaction between microbes and cancer can be through contact-dependent, contact-independent, and/or immunological interactions. Profiling the microbiome in the context of cancer may provide prognostic and/or diagnostic options for patients. However, interactions between the microbiome and mutant p53 in LFS has not been studied to date. We induced dysbiosis using a combination of antibiotics in LFS mice harbouring the heterozygous Trp53 R172H mutation. Following 7 days of treatment, we challenged mice with subcutaneous injections of the MC38 colon adenocarcinoma cell line. We observed an increase in tumour volume in LFS mice treated with antibiotics; this change was not observed in p53 wildtype mice. These findings highlight potentially unique interactions between mutant p53 and the microbiome which influence tumour growth in the context of LFS. We also found that LFS mice treated with metformin have smaller tumours compared to untreated mice. A particular genus of bacteria, Faecalibaculum sp., was found to be upregulated in a cohort of metformin treated mice, and the abundance of this bacterium is inversely proportional to tumour volume. Zagato et al. have shown that Faecalibaculum rodentium has anti-tumourigenic properties through the production of short-chain fatty acid (SCFA). Altogether, these observations suggest that microbes may influence tumour growth in LFS mice. The study of interactions between the microbiome and mutant p53 and the influence of these interactions on cancer development in LFS may, with further study, provide avenues of prognostic and/or diagnostic interest. Differences in the microbiome in cancer-affected and cancer-free LFS patients may also introduce the possibility to exploit the microbiome for treatment and/or preventative purposes in these patients. Citation Format: Noel Wei Ong, Camilla Maria Giovino, Nicholas William Fischer, Pamela Psarianos, David Malkin. Investigating the interaction between the microbiome and mutant p53 in Li-Fraumeni Syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3047.

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Fischer, Nicholas W., Brianne Laverty, Ran Kafri, Kara N. Maxwell, Emma R. Woodward, Christian Kratz et David Malkin. « Abstract 6198 : TP53 mutational clusters stratify the Li-Fraumeni syndrome spectrum ». Cancer Research 84, n^o 6_Supplement (22 mars 2024) : 6198. http://dx.doi.org/10.1158/1538-7445.am2024-6198.

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Abstract Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition disorder caused by germline variants in the TP53 tumor suppressor gene. LFS has recently been redefined as a ‘spectrum’ disorder to reflect the highly variable cancer types with largely unpredictable ages-of-onset and disease severity. The broad functional gradient associated with different TP53 variants is thought to contribute to LFS heterogeneity, although it is still poorly understood and there is an unmet clinical need for risk stratification strategies to improve variant interpretation and patient care. Here, we performed an unsupervised cluster analysis leveraging p53 mutagenesis datasets (Kato et al., 2003 & Giacomelli et al., 2018) that revealed five TP53 mutational clusters with unique mutation patterns, structural features, and functional consequences. Stratifying germline carriers based on the five clusters exposed important clinical characteristics to consider for patient management, such as ages-of-onset, tumor type development, and survival outcomes. In particular, we discovered an osteosarcoma-prone subgroup comprised of monomeric mutant p53 carriers with aggressive cancer phenotypes. We also identified a cluster of TP53 variants found more often in non-cancer and healthy older populations, and carriers of these variants that developed cancer had less “LFS-like” phenotypes including an older age-of-onset and a significantly higher frequency of colorectal cancers. Remarkably, our TP53 variant clustering strategy could also stratify breast cancer survival among germline carriers. This work provides a new framework to delineate the LFS spectrum toward the development of machine learning-based approaches for personalized cancer surveillance plans. Citation Format: Nicholas W. Fischer, Brianne Laverty, Ran Kafri, Kara N. Maxwell, Emma R. Woodward, Christian Kratz, David Malkin. TP53 mutational clusters stratify the Li-Fraumeni syndrome spectrum [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6198.

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Renaux-Petel, Mariette, Françoise Charbonnier, Jean-Christophe Théry, Pierre Fermey, Gwendoline Lienard, Jacqueline Bou, Sophie Coutant et al. « Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome ». Journal of Medical Genetics 55, n^o 3 (25 octobre 2017) : 173–80. http://dx.doi.org/10.1136/jmedgenet-2017-104976.

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BackgroundDevelopment of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germline TP53 mutation. The aim of this study was to determine the contribution of de novo and mosaic mutations to LFS.Methods and resultsAmong 328 unrelated patients harbouring a germline TP53 mutation identified by Sanger sequencing and/or QMPSF, we could show that the mutations had occurred de novo in 40 cases, without detectable parental age effect. Sanger sequencing revealed two mosaic mutations in a child with ACC and in an unaffected father of a child with medulloblastoma. Re-analysis of blood DNA by next-generation sequencing, performed at a depth above 500X, from 108 patients suggestive of LFS without detectable TP53 mutations, allowed us to identify 6 additional cases of mosaic TP53 mutations, in 2/49 children with ACC, 2/21 children with CPT, in 1/31 women with breast cancer before age 31 and in a patient who developed an osteosarcoma at age 12, a breast carcinoma and a breast sarcoma at age 35.ConclusionsThis study performed on a large series of TP53 mutation carriers allows estimating the contribution to LFS of de novo mutations to at least 14% (48/336) and suggests that approximately one-fifth of these de novo mutations occur during embryonic development. Considering the medical impact of TP53 mutation identification, medical laboratories in charge of TP53 testing should ensure the detection of mosaic mutations.

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Rocca, Valentina, Giovanni Blandino, Lucia D’Antona, Rodolfo Iuliano et Silvia Di Agostino. « Li–Fraumeni Syndrome : Mutation of TP53 Is a Biomarker of Hereditary Predisposition to Tumor : New Insights and Advances in the Treatment ». Cancers 14, n^o 15 (27 juillet 2022) : 3664. http://dx.doi.org/10.3390/cancers14153664.

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Li–Fraumeni syndrome (LFS) is a rare familial tumor predisposition syndrome with autosomal dominant inheritance, involving germline mutations of the TP53 tumor suppressor gene. The most frequent tumors that arise in patients under the age of 45 are osteosarcomas, soft-tissue sarcomas, breast tumors in young women, leukemias/lymphomas, brain tumors, and tumors of the adrenal cortex. To date, no other gene mutations have been associated with LFS. The diagnosis is usually confirmed by genetic testing for the identification of TP53 mutations; therefore, these mutations are considered the biomarkers associated with the tumor spectrum of LFS. Here, we aim to review novel molecular mechanisms involved in the oncogenic functions of mutant p53 in LFS and to discuss recent new diagnostic and therapeutic approaches exploiting TP53 mutations as biomarkers and druggable targets.

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Frebourg, Thierry, Svetlana Bajalica Lagercrantz, Carla Oliveira, Rita Magenheim et D. Gareth Evans. « Guidelines for the Li–Fraumeni and heritable TP53-related cancer syndromes ». European Journal of Human Genetics 28, n^o 10 (26 mai 2020) : 1379–86. http://dx.doi.org/10.1038/s41431-020-0638-4.

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Abstract Fifty years after the recognition of the Li–Fraumeni syndrome (LFS), our perception of cancers related to germline alterations of TP53 has drastically changed: (i) germline TP53 alterations are often identified among children with cancers, in particular soft-tissue sarcomas, adrenocortical carcinomas, central nervous system tumours, or among adult females with early breast cancers, without familial history. This justifies the expansion of the LFS concept to a wider cancer predisposition syndrome designated heritable TP53-related cancer (hTP53rc) syndrome; (ii) the interpretation of germline TP53 variants remains challenging and should integrate epidemiological, phenotypical, bioinformatics prediction, and functional data; (iii) the penetrance of germline disease-causing TP53 variants is variable, depending both on the type of variant (dominant-negative variants being associated with a higher cancer risk) and on modifying factors; (iv) whole-body MRI (WBMRI) allows early detection of tumours in variant carriers and (v) in cancer patients with germline disease-causing TP53 variants, radiotherapy, and conventional genotoxic chemotherapy contribute to the development of subsequent primary tumours. It is critical to perform TP53 testing before the initiation of treatment in order to avoid in carriers, if possible, radiotherapy and genotoxic chemotherapies. In children, the recommendations are to perform clinical examination and abdominal ultrasound every 6 months, annual WBMRI and brain MRI from the first year of life, if the TP53 variant is known to be associated with childhood cancers. In adults, the surveillance should include every year clinical examination, WBMRI, breast MRI in females from 20 until 65 years and brain MRI until 50 years.

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Shin, Seung Jun, Jialu Li, Jing Ning, Jasmina Bojadzieva, Louise C. Strong et Wenyi Wang. « Bayesian estimation of a semiparametric recurrent event model with applications to the penetrance estimation of multiple primary cancers in Li-Fraumeni syndrome ». Biostatistics 21, n^o 3 (14 novembre 2018) : 467–82. http://dx.doi.org/10.1093/biostatistics/kxy066.

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Summary A common phenomenon in cancer syndromes is for an individual to have multiple primary cancers (MPC) at different sites during his/her lifetime. Patients with Li-Fraumeni syndrome (LFS), a rare pediatric cancer syndrome mainly caused by germline TP53 mutations, are known to have a higher probability of developing a second primary cancer than those with other cancer syndromes. In this context, it is desirable to model the development of MPC to enable better clinical management of LFS. Here, we propose a Bayesian recurrent event model based on a non-homogeneous Poisson process in order to obtain penetrance estimates for MPC related to LFS. We employed a familywise likelihood that facilitates using genetic information inherited through the family pedigree and properly adjusted for the ascertainment bias that was inevitable in studies of rare diseases by using an inverse probability weighting scheme. We applied the proposed method to data on LFS, using a family cohort collected through pediatric sarcoma patients at MD Anderson Cancer Center from 1944 to 1982. Both internal and external validation studies showed that the proposed model provides reliable penetrance estimates for MPC in LFS, which, to the best of our knowledge, have not been reported in the LFS literature.

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Padilla, Hannah, Ivan Carabenciov, Joon Uhm et Bryan Neth. « NCOG-38. UNDERSTANDING GLIOMA IN LI-FRAUMENI SYNDROME : HIGHLIGHTING THE VALUE OF SCREENING AND GENE SEQUENCING ». Neuro-Oncology 25, Supplement_5 (1 novembre 2023) : v222. http://dx.doi.org/10.1093/neuonc/noad179.0851.

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Abstract Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant disorder characterized by a germline mutation in the TP53 gene that confers an increased risk of developing cancers, including brain tumors. There is continued need to understand how LFS diagnosis impacts clinical management and outcomes of gliomas. We report the clinical course of two patients from our Neuro-Oncology. Patient 1 is a male who was diagnosed with a low-grade astrocytoma, IDH1 mutant at age 20 status post gross total resection. Given radiographic concern for tumor progression, he underwent re-resection 8 years later. Pathology showed gliosis with TP53-mutant cells. Next-generation sequencing (NGS) was positive a germline TP53 mutation, consistent with LFS. He is currently in surveillance 12 years after diagnosis without need for radiation or chemotherapy. Patient 2 is a female who was diagnosed with glioblastoma, IDH wildtype, MGMT promoter unmethylated at age 40. She was asymptomatic at the time of diagnosis as the tumor was found during routine screening. She underwent gross total resection, radiation with concurrent and adjuvant temozolomide. She is now 5 years from last treatment without recurrence. These cases illustrate the clinical spectrum of glioma in LFS. Both patients have had prolonged periods of survival without progression, even accounting for respective tumor type. Patient 1 was only diagnosed with LFS after radiographic concerns for progression. Using NGS to diagnosis LFS was clinically important, as previous reports have shown greater propensity for malignant transformation of low-grade glioma in LFS. Patient 2 was diagnosed with glioblastoma during screening and has had no recurrence. This highlights the value of early diagnosis and treatment of gliomas in patients with LFS, even if asymptomatic at discovery. Further research is needed to understand the clinical spectrum of glioma in LFS and to optimize the care of this unique patient population.

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