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Articoli di riviste sul tema "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 e Patricia Ashton-Prolla. "Pediatric cancer and Li-Fraumeni/Li-Fraumeni-like syndromes: a review for the pediatrician". Revista da Associação Médica Brasileira 61, n. 3 (giugno 2015): 282–89. http://dx.doi.org/10.1590/1806-9282.61.03.282.
Testo completoAbstract (sommario):
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 e Momir Sarac. "Li-Fraumeni syndrome: Case report". Vojnosanitetski pregled, n. 00 (2022): 36. http://dx.doi.org/10.2298/vsp211102036s.
Testo completoAbstract (sommario):
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. 16_suppl (1 giugno 2024): 10613. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.10613.
Testo completoAbstract (sommario):
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 e Nada Vuckovic. "Li-fraumeni syndrome: A case report". Vojnosanitetski pregled 71, n. 12 (2014): 1159–62. http://dx.doi.org/10.2298/vsp1412159i.
Testo completoAbstract (sommario):
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 e Sarbar Napaki. "An Uncommon Presentation of Li Fraumeni Syndrome". Journal of Medical Research and Surgery 1, n. 2 (18 marzo 2020): 1–3. http://dx.doi.org/10.52916/jmrs204008.
Testo completoAbstract (sommario):
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. 21 (20 luglio 2015): 2345–52. http://dx.doi.org/10.1200/jco.2014.59.5728.
Testo completoAbstract (sommario):
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 e Yukiko Tsunematsu. "Medical guidelines for Li–Fraumeni syndrome 2019, version 1.1". International Journal of Clinical Oncology 26, n. 12 (11 ottobre 2021): 2161–78. http://dx.doi.org/10.1007/s10147-021-02011-w.
Testo completoAbstract (sommario):
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 e David Malkin. "Abstract 3364: Diagnosing Li-Fraumeni syndrome from the somatic genome". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 3364. http://dx.doi.org/10.1158/1538-7445.am2022-3364.
Testo completoAbstract (sommario):
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. 18 (20 giugno 2010): 3008–14. http://dx.doi.org/10.1200/jco.2009.27.2112.
Testo completoAbstract (sommario):
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 e Lazar Glisic. "Li-Fraumeni Syndrome With Six Primary Tumors—Case Report". Case Reports in Oncological Medicine 2024 (10 maggio 2024): 1–7. http://dx.doi.org/10.1155/2024/6699698.
Testo completoAbstract (sommario):
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.
Tesi sul tema "Syndrome de Li-Fraumeni (LFS)"
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Brown, Lauren T. R. "Alterations of PTEN in Li-Fraumeni syndrome (LFS) and solid tumors common to the syndrome". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0006/MQ46060.pdf.
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Louis, Jeanne. "Syndrοme de Li-Fraumeni : apprοches fοnctiοnnelles visant à appréhender la variabilité génοtypique et phénοtypique". Electronic Thesis or Diss., Normandie, 2025. http://www.theses.fr/2025NORMR002.
Testo completoAbstract (sommario):
Le syndrome de Li-Fraumeni (LFS) prédispose les porteurs de variations pathogènes de TP53 à un large spectre de tumeurs dès l’enfance. La variabilité phénotypique du LFS complique la prise en charge des patients et peut s’expliquer en partie par le type de variations de TP53, mais également par l'influence de facteurs modificateurs génétiques. Afin d’évaluer ces facteurs modificateurs, il est nécessaire de mettre au point des tests fonctionnels adaptés.L’activité des isoformes de p53 suggère qu’elles pourraient agir comme facteurs modificateurs du LFS. C’est pourquoi nous avons mis au point des techniques pour l’analyse des transcrits alternatifs, présentées dans la première partie de ces travaux de thèse. Si nos résultats ont montré que ces techniques n’étaient pas adaptées pour répondre à cette hypothèse, elles nous ont néanmoins permis d’identifier un nouveau transcrit physiologique, non décrit dans la littérature, augmenté chez une patiente porteuse d’une variation située sur le site accepteur d’épissage du dernier exon de TP53. Ce transcrit démontre l’existence d’un épissage alternatif du dernier exon de TP53 avec un exon terminal alternatif situé à plus de 2 kb en aval.Afin d’aider à la classification des variations de TP53, notre laboratoire évalue l’activité transcriptionnelle de p53 dans le contexte génétique du patient. Ce test ne permet donc pas de s’affranchir de l’influence potentielle des facteurs modificateurs génétiques individuels. C’est pourquoi, dans la deuxième partie de ces travaux de thèse, nous avons mis au point un modèle cellulaire de cellules souches pluripotentes induites humaines permettant d’étudier les variations de TP53 insérées par CRISPR-Cas9 dans un fond génétique commun. Ces travaux soulignent l’importance de l’expression de TP53, notamment pour l’étude des variations dont la pénétrance est moindre par rapport aux variations « hot-spot ». Par ailleurs, nous montrons que les variations en phase exercent un impact différentiel sur l’activité fonctionnelle de p53, selon le domaine protéique dans lequel elles se situent. L’avantage de notre modèle réside également sur son hétérozygotie pour PEX4 sur lequel nous avons pu insérer une seconde variation, ici le polymorphisme p.(Pro47Ser) inséré en trans d’une variation pathogène. Nos résultats soulignent l’importance du contexte génétique dans l’analyse des variations de TP53. L’ensemble de ces travaux de thèse mettent en lumière la nécessité d’étudier l’activité transcriptionnelle de p53 dans un contexte physiologique, sans surexpression, dans le but de mieux comprendre ce syndrome et d’optimiser la prise en charge des patients LFSLi-Fraumeni Syndrome (LFS) predisposes carriers of pathogenic TP53 variants to a wide spectrum of cancers throughout life. The phenotypic variability of LFS complicates patient management and can be partly attributed to the type of TP53 variant, as well as the influence of genetic modifier factors. To evaluate these modifier factors, it is essential to develop suitable functional tests.The activity of p53 isoforms suggests that they may act as modifier factors in LFS. Consequently, we developed assays for analyzing alternative transcripts, as presented in the first part of this work. While our results demonstrated that these assays were not well-suited to addressing this specific hypothesis, they nevertheless led us to the discovery of a novel physiological transcript not previously described in the literature. This transcript was found to be increased in a patient carrying a variant located at the splice acceptor site of TP53’s last exon, revealing an alternative splicing event involving TP53’s final exon and an alternative terminal exon located more than 2 kb downstream.To facilitate the classification of TP53 variants, our laboratory evaluates p53’s transcriptional activity in the patient’s specific genetic context. However, this approach does not allow us to fully disentangle the potential influence of individual genetic modifier factors. Therefore, in the second part of this work, we developed a human-induced pluripotent stem cell model to study TP53 variants introduced by CRISPR-Cas9 within a standardized genetic background. Our findings highlight the importance of physiological TP53 expression, particularly for studying variants with lower penetrance compared to "hot-spot" variants. Additionally, we show that in-frame variants exert differential impacts on p53’s functional activity, depending on the protein domain in which they are located. The advantage of our model also lies in its heterozygosity for PEX4, into which we were able to insert a second variant, in this case, the p.(Pro47Ser) polymorphism, inserted in trans with a pathogenic variant. Our results highlight the importance of the genetic context in the analysis of TP53 variants. This thesis work emphasizes the necessity of studying p53 transcriptional activity in a physiological context, without overexpression, with the aim of improving our understanding of this syndrome and optimizing the management of LFS patients
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VIALLE, JEAN-MICHEL. "P53 et les anomalies chromosomiques de la tumorogenese : l'exemple du syndrome de li et fraumeni". Lyon 1, 1994. http://www.theses.fr/1994LYO1M178.
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Spees, Colleen K. "Dysregulation of p53 Gene Expression in Human Prostate Carcinogenesis and Its Relationship to Angiogenesis". The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1313523656.
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Lavagna, Thierry. "Syndrome de li-fraumeni : analyse d'une serie de douze familles". Lyon 1, 1992. http://www.theses.fr/1992LYO1M012.
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Warneford, Sally. "Genetic and biological studies in a Li-Fraumeni syndrome family". Thesis, The University of Sydney, 1993. https://hdl.handle.net/2123/26604.
Testo completoAbstract (sommario):
This thesis presents various clinical, genetic and biological aspects of a cancer-prone family. Two probands were studied at the initiation of the study: a 36-year-old female with infiltrating ductal breast carcinoma and a recent history of adrenocortical carcinoma (ACC), and her 21/2-year-old son, also with ACC. The occurrence of the latter, an extremely rare tumour, in two members of the one family prompted speculation that these two individuals may belong to a Li-Fraumeni cancer syndrome (LFS) family. ACC is a hallmark tumour of this particular cancer family syndrome, which also includes tumours affecting such diverse tissues as breast, soft-tissue, bone, brain and haematopoietic cells. A pedigree spanning five generations was compiled using family recollections and medical records of cancer. A comparison of the pedigree for this family with the clinical requirements for LFS and a genetic analysis confirming that the cancer predisposition was inherited in an autosomal dominant fashion showed that this was indeed an LFS cancer family.
Because the predisposing lesion for LFS had not yet been discovered at the initiation of this study. examination of the cancer inheritance in this family was of interest. In order to provide material for long-term studies and to enable a preliminary characterisation of tumourigenesis in the probands, attempts were made to grow tumour and constitutional cells from both probands in culture. The primary breast carcinoma grew for a brief period only, before stromal fibroblast-like cells took over the culture. A bony metastasis of the same tumour, however, was found to grow as non—adherent multicellular spheroids which persisted longer in culture, probably indicative of the progressive changes that occurred in vivo. The stromal fibroblasts were found to be normal and thence served as a constitutional control for the breast carcinoma.
The boy's adrenocortical carcinoma recurred twice before his death at age 6 years and it was from the first and second recurrences of his tumour that cells were cultured. The cells which grew were heterogeneous in morphology and were not immortalised. There were also morphological and immunocytochemical differences between the cell strains derived from the first and second relapses. These differences were thought to indicate both the heterogeneous nature of the adrenocortical carcinoma and to represent progressive changes in tumourigenesis. Normal abdominal skin fibroblasts were cultured as constitutional controls.
In order to investigate the predisposing lesion for the cancer predisposition, the p53 tumour suppressor gene was selected as a candidate, based on its frequent involvement in sporadic tumours of the same type as those found in LFS patients and also the finding that transgenic mice expressing a mutant p53 allele showed a higher frequency of malignancy than normal controls. The involvement of the p53 gene was examined by Northern and Southern blot analysis, 81 nuclease mapping, and genomic DNA and cDNA PCR/sequencing. An additional larger transcript was found in both tumour and constitutional RNA from the probands, and in constitutional RNA from some obligate carriers, that was not present in controls and unaffected individuals. This was thought to be indicative of an underlying germline alteration to the p53 gene in those individuals with the larger transcript. The size discrepancy in the transcripts was not caused by a genomic rearrangement but was found to be due to the retention of all or most of intron 4 in the mature mRNA because of a germline point mutation in the intron 4 5' splice donor site (at the last base o fexon 4) of one p53 allele.
The frequent occurrence of stop codons in intron 4 ensured that if a protein could be produced from the larger transcript. it would be truncated and the p53 immunoprecipitations gave some evidence for the existence of a truncated protein product. Interestingly. the mutation, a G to A transition, appeared to produce only a partial disruption to splicing in Northern and cDNA PCR/sequencing analysis, with a proportion of the transcripts produced from the mutant allele being normally spliced. The mutation was in the last base of exon 4 which is also the last base of codon 125. Because of coding degeneracy, it was found that these normally-spliced mutant transcripts would not result in an amino acid substitution when translated implying that this mutation, rather than abolishing the functionality of the mutant allele could result in a reduction in p53 levels. Thus the mutation is unusual in that it is potentially weaker in its effect than most other sporadic and germ-line p53 mutations. This is the first report of a germ-line splicing mutation in the p53 gene and appears to be the most 5' of the LFS germ-line mutations reported.
The secondary events in tumourigenesis in both of the probands. in particular the fate of the remaining p53 allele, were investigated. Evidence from Northern and PCR/sequence analysis suggested that the second p53 allele had been lost during development of both the breast carcinoma and the ACC in the probands, with retention of the mutant allele. Both tumours showed extensive karyotypic abnormalities including aneuploidy, with translocations, deletions and both consistent and random chromosome losses. Some of the consistent chromosomal losses were thought to be linked to the loss of tumour suppressor genes involved in the tumoun'genic process. Other genetic events included the over-expression of the dominantly-acting nuclear oncogene c-myc in the breast carcinoma, which is linked to a highly proliferative tumour and a poor prognosis, and the over-expression of Rb in the ACC. The over-expression of Rb was carried through to over-production of an apparently wild-type pr, probably due to disruption of the Rb functional pathway. The over-expression of Rb was an unusual finding as this gene is normally mutated or lost in tumours. This gene over-expression and protein overproduction in the ACC could also have been influenced by the lack of sufficient functional p53, which would normally down-regulate the expression of Rb. In contrast to the reports of others, the constitutional fibroblasts of both probands did not show an increased rate of spontaneous immortalisation nor did they show karyotypic abnormalities, perhaps because of the weak nature of the germ-line mutation uncovered in this family.
Thus, in this project a cancer-prone family was identified, and constitutional and tumour cells from two probands were cultured for analysis. A putative predisposing lesion for the cancer-predisposition in an LFS cancer family was discovered in the p53 gene. The mutation was novel in both its location (in exon 4 rather than the hotspot for LFS mutations, exon 7) and type (a splicing mutation rather than the more common missense mutation). The tumourigenic process in the two probands was investigated and some of the secondary genetic events in the tumours of the probands were uncovered, including the loss of the remaining allele of the p53 gene, overexpression of C-myc and Rb.
Please note that the literature reviewed in this thesis is current up to February 1993.
7
Thery, Jean-Christophe. "Détection et contribution de variants rares constitutionnels dans les formes précoces de cancer du sein : Apports du Séquençage de Nouvelle Génération. Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome Germline mutations of inhibins in early-onset ovarian epithelial tumors". Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR111.
Testo completoAbstract (sommario):
Si le syndrome de prédisposition héréditaire au cancer du sein et de l’ovaire constitue uneentité reconnue et supportée par l’identification de variations délétères sur les gènes BRCA1,BRCA2, PALB2, RAD51C et RAD51D, et si le cancer du sein de la femme jeune (avant 31 ans) estintégré dans le spectre du syndrome de Li-Fraumeni lié aux altérations de TP53, une large fractiondes patientes adressées en consultation d’oncogénétique pour ce motif demeure orpheline dediagnostic moléculaire. La connaissance du génome humain et l’avènement du séquençage denouvelle génération ont permis des avancées considérables, notamment dans l’observation de latrès grande variabilité du génome et de la survenue de variations de novo.Nous avons ainsi appliqué ces outils et ces concepts au cancer du sein de la femmejeune, afin de tenter d’identifier de nouveaux déterminants moléculaires constitutionnels. Dansune première approche basée sur la réalisation d’exomes soustractifs pour des trios parents- enfant, nous avons recherché des variants de novo délétères et effectivement identifié un variantrare de novo et délétère sur le gène INHBA dans le contexte d’un cancer de l’ovaire chez unejeune femme. Cette approche n’a cependant pu être reproduite dans le contexte d’un cancer dusein précoce. Nous avons également tenté une approche par exomes comparatifs dans unefamille remarquable avec survenue de cancers du sein précoces sur trois générations, sansvariation délétère identifiée commune à ces individus. Dans une seconde approche basée surun panel de 201 gènes impliqués dans la cancérogenèse, nous avons tenté d’identifier desvariants délétères ou des enrichissements en variants rares dans une cohorte de cancers du seinprécoces. Nous avons identifié une variation en mosaïque de TP53, sans autre détection devariations formellement délétères parmi 30 patientes atteintes de cancers du sein avant 31 ans.Un enrichissement non significatif en variants rares affectant les voies de la réparation de l’ADN aété néanmoins mis en évidence, suggérant des études plus larges ciblant ces voies. Enfin, nousavons recherché spécifiquement des variants de novo en mosaïque de TP53 dans lecontexte du cancer du sein de la femme jeune ou de cancers pédiatriques, et démontré ainsi laprévalence relativement importante de ces évènements. Ces observations supportent la nécessitéd’user d’un séquençage de forte profondeur et de ne pas restreindre les indications d’analyses deTP53 aux seules situations familiales évocatricesDespite previous identifications of deleterious variants on BRCA1, BRCA2, PALB2,RAD51C and RAD51D supporting the hereditary breast and ovarian cancer syndrom, and thecontribution of TP53 mutations in very early-onset breast carcinomas, a large fraction of patientssuggestive of Medelian disease remains without molecular diagnosis. In the past years,sequencing of the Human genome and next-generation sequencing offered major advances, inparticular in the field of genome variability and de novo variants.We applied these new tools and concepts in the context of very early-onset breastcarcinomas, in order to identify new molecular germline determinants. First, we dealt withsoustractive exomes, in parents - child trios, and succeed in the identification of a deleterious denovo variant in the INHBA gene, in the context of very early-onset of ovarian cancer. However, wehave failed with this approach in a second trio with an index affected by early-onset breastcarcinoma. We also tried a comparative exome sequencing approach in a remarkable pedigreewith multiple probands affected by early-onset breast carcinomas, without identification of ashared deleterious variant. Secondly, we used a home-made 201 genes panel assuming thatgenes somatically affected in cancers might be altered in inherited conditions. We analyzed acohort of very early-onset breast carcinomas, and identified a mosaic TP53 variation. Moreover,we identified some interesting candidate variants and observed a non-significant trend of rarevariants enrichment in the DNA repair pathway. Finally, we designed a specific TP53 gene capturein order to detect mosaic variants in pediatric cancers and very early-onset breast carcinomas.We confirmed the clinically significant prevalence of these alterations, which support TP53analysis in these conditions even in sporadic presentations
8
Hütten, Michele Oliveira. "Atuação da mutação R337H em TP53 em pacientes de Li-Fraumeni em autofagia, senescência e função mitocondrial". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/173139.
Testo completoAbstract (sommario):
Introdução: As síndromes de Li-Fraumeni (LFS) e Li-Fraumeni Like (LFL) são síndromes hereditárias de predisposição a câncer frequentemente associadas à mutações germinativas no gene TP53. Devido à importância de p53 e diversidade de processos celulares que ela regula, várias vias de sinalização podem ser afetadas pela doença. Nesse estudo discutimos o impacto da mutação p.R337H na proliferação, senescência, autofagia, população e funcionalidade mitocondrial. Métodos: As taxas de proliferação foram avaliadas pelo ensaio de Population Doubling. Os experimentos de senescência, autofagia, massa total e funcionalidade mitocondrial foram realizados por citometria de fluxo. Resultados: As células contendo a mutação proliferaram mais do que as células controle. Além disso, as células mutadas não ativaram autofagia sob tratamento de Rapamicina nem senescência sob tratamento de Doxorubicina ou Cisplatina e exibiram maior população mitocondrial, mas com funcionalidade inalterada após os tratamentos. Conclusão: os dados sugerem que a mutação p.R337H em TP53 afeta a indução de senescência realizada por p53 e suas funções pró-autofágicas, bem como seu controle. As células mutadas proliferam mais do que células sem mutação em TP53 e exibiram maior massa mitocondrial sem perda de funcionalidade após o tratamento com Doxorubicina.Background: Li-Fraumeni (LFS) and Li-Fraumeni Like (LFL) syndromes are hereditary cancer predisposition syndromes frequently associated with germline mutation in TP53. Due to the importance of the protein p53 and its regulation of several important cellular processes, impairment in some pathways can be implicated. Here we discuss the impact of p.R337H TP53 mutation on proliferation, senescence, autophagy, mitochondrial population and functionality. Methods: Growth rates were assayed with Population Doubling assay. Senescence and autophagy were assessed through flow cytometry and functionality and total population of mitochondria were also analyzed through flow cytometry. Results: mutated cells proliferated more than control cells. TP53 mutated cells didn’t build up autophagy under Rapamycin treatmend nor senescence under Doxorubicin or Cisplatin treatments and showed more mitochondrial mass, but no alterations in mitochondrial functionality after Doxorubicin treatment. Conclusion:data suggests that p.R337H TP53 mutation affect senescence induction by p53 and pro-autophagic actions of p53. Mutated cells proliferate more than control cells and exhibited larger mitochondrial mass without effects in their functionality in response to Doxorubicin treatment.
9
Jaber, Sara. "Impact des dérégulations de p53 : du syndrome Li-Fraumeni aux syndromes d'insuffisance médullaire héréditaire". Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066242/document.
Testo completoAbstract (sommario):
TP53 est un gène suppresseur de tumeur muté dans la moitié des cancers humains. La plupart des mutations de TP53 affectent le domaine de liaison à l’ADN de la protéine, et sont situées au niveau de sept « hotspot » mutationnels. Parmi elles, la mutation Y220C est retrouvée dans 100 000 nouveaux cas de cancer par an et dans 10 familles Li-Fraumeni de prédisposition au cancer. Pour étudier cette mutation in vivo, j’ai créé au cours de ma thèse le modèle murin exprimant une protéine p53 portant la mutation Y217C équivalente à la Y220C humaine. J’ai pu démontrer que non seulement la mutation inactive la fonction de la protéine mais qu’elle semble également conférer de nouvelles fonctions oncogéniques. Plus intéressant encore, ce modèle constitue un très bon outil pour le test d’une nouvelle stratégie thérapeutique spécifique de cette mutation. Par ailleurs, le modèle murin p53∆31/∆31 a été créé dans notre laboratoire et a permis de démontrer in vivo le rôle de régulateur négatif du domaine C-terminal de p53 sur son activité. Au cours de mes travaux de recherche, j’ai pu montrer que p53 joue un rôle dans la régulation de nouvelles voies cellulaires chez la souris et chez l’Homme, et établi le mécanisme en jeu dans cette régulation. De façon surprenante, ces fonctions insoupçonnées sont impliquées dans la promotion de l’instabilité génétique et une activité accrue de p53 peut entraîner des maladies d’insuffisance médullaire prédisposant au cancer. Nos observations ont donc des retombées fondamentales mais également cliniques pour le diagnostic de ces maladies ainsi que pour les stratégies anti-tumorales selon le statut de p53TP53 is a tumor suppressor gene mutated in half of human cancers. Most of TP53 mutations affect the core DNA binding domain of the protein, and are located on seven « hotspot » residues. Among them, the Y220C mutation is found in 100 000 new cancer cases per year and in 10 Li-Fraumeni families of cancer predisposition. To study this mutation in vivo, I created a mouse model carrying the Y217C mutation, equivalent to the human Y220C. I showed that not only this mutation inactivates the function of the protein, but that it also confers new oncogenic functions. Moreover, this model is a great tool to evaluate the efficiency of a novel anti-tumoral strategy in vivo. Furthermore, the mouse p53∆31/∆31 model was created in our team and allowed us to demonstrate the negative regulatory role of the C-terminus of p53 in vivo. I used this model to discover the implication of p53 in the regulation of unsuspected cellular pathways in mice but also in humans, and to establish the mechanism of regulation. Surprisingly, these functions are responsible for the promotion of the genomic instability and p53’s high activity can cause bone marrow failure syndromes that predispose to cancer. Our observations have both fundamental and clinical impact for the diagnosis of these diseases and for the therapeutic anti-tumoral strategies according to p53’s status
10
Jaber, Sara. "Impact des dérégulations de p53 : du syndrome Li-Fraumeni aux syndromes d'insuffisance médullaire héréditaire". Electronic Thesis or Diss., Paris 6, 2016. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2016PA066242.pdf.
Testo completoAbstract (sommario):
TP53 est un gène suppresseur de tumeur muté dans la moitié des cancers humains. La plupart des mutations de TP53 affectent le domaine de liaison à l’ADN de la protéine, et sont situées au niveau de sept « hotspot » mutationnels. Parmi elles, la mutation Y220C est retrouvée dans 100 000 nouveaux cas de cancer par an et dans 10 familles Li-Fraumeni de prédisposition au cancer. Pour étudier cette mutation in vivo, j’ai créé au cours de ma thèse le modèle murin exprimant une protéine p53 portant la mutation Y217C équivalente à la Y220C humaine. J’ai pu démontrer que non seulement la mutation inactive la fonction de la protéine mais qu’elle semble également conférer de nouvelles fonctions oncogéniques. Plus intéressant encore, ce modèle constitue un très bon outil pour le test d’une nouvelle stratégie thérapeutique spécifique de cette mutation. Par ailleurs, le modèle murin p53∆31/∆31 a été créé dans notre laboratoire et a permis de démontrer in vivo le rôle de régulateur négatif du domaine C-terminal de p53 sur son activité. Au cours de mes travaux de recherche, j’ai pu montrer que p53 joue un rôle dans la régulation de nouvelles voies cellulaires chez la souris et chez l’Homme, et établi le mécanisme en jeu dans cette régulation. De façon surprenante, ces fonctions insoupçonnées sont impliquées dans la promotion de l’instabilité génétique et une activité accrue de p53 peut entraîner des maladies d’insuffisance médullaire prédisposant au cancer. Nos observations ont donc des retombées fondamentales mais également cliniques pour le diagnostic de ces maladies ainsi que pour les stratégies anti-tumorales selon le statut de p53TP53 is a tumor suppressor gene mutated in half of human cancers. Most of TP53 mutations affect the core DNA binding domain of the protein, and are located on seven « hotspot » residues. Among them, the Y220C mutation is found in 100 000 new cancer cases per year and in 10 Li-Fraumeni families of cancer predisposition. To study this mutation in vivo, I created a mouse model carrying the Y217C mutation, equivalent to the human Y220C. I showed that not only this mutation inactivates the function of the protein, but that it also confers new oncogenic functions. Moreover, this model is a great tool to evaluate the efficiency of a novel anti-tumoral strategy in vivo. Furthermore, the mouse p53∆31/∆31 model was created in our team and allowed us to demonstrate the negative regulatory role of the C-terminus of p53 in vivo. I used this model to discover the implication of p53 in the regulation of unsuspected cellular pathways in mice but also in humans, and to establish the mechanism of regulation. Surprisingly, these functions are responsible for the promotion of the genomic instability and p53’s high activity can cause bone marrow failure syndromes that predispose to cancer. Our observations have both fundamental and clinical impact for the diagnosis of these diseases and for the therapeutic anti-tumoral strategies according to p53’s status
Libri sul tema "Syndrome de Li-Fraumeni (LFS)"
1
Brown, Lauren T. R. Alterations of PTEN in Li-Fraumeni syndrome (LFS) and solid tumors common to the syndrome. Ottawa: National Library of Canada, 1999.
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2
Williams, Kaye Janine. Tumourigenesis mechanisms in Li-Fraumeni syndrome. Manchester: University of Manchester, 1996.
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3
Parker, James N., e Philip M. Parker. Li-Fraumeni syndrome: A bibliography and dictionary for physicians, patients, and genome researchers [to Internet references]. San Diego, CA: ICON Health Publications, 2007.
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4
Kahlenberg, Morton S. Hereditable cancer syndromes: Evaluation, treatment and the role of the surgical oncologist. Philadelphia, Pa: Saunders, 2009.
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5
Plotkin, Scott R., Jaclyn A. Biegel, David Malkin, Robert Martuza e D. Gareth Evans. Familial tumour syndromes: neurofibromatosis, schwannomatosis, rhabdoid tumour predisposition, Li–Fraumeni syndrome, Turcot syndrome, Gorlin syndrome, and Cowden syndrome. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199651870.003.0015.
Testo completoAbstract (sommario):
‘Familial tumour syndromes’ reviews some of the genetic syndromes associated with an increased incidence of nervous system tumours, including neurofibromatosis 1, neurofibromatosis 2, schwannomatosis, rhabdoid tumour predisposition, Li–Fraumeni syndrome, Turcot syndrome, Gorlin syndrome, and Cowden syndrome. The chapter reviews the epidemiology of these rare conditions with discussion of current diagnostic criteria. It reviews the genetic basis and pathogenesis of the conditions as well as the availability of genetic testing. It covers the clinical aspects of these conditions, including clinical presentation, associated nervous system tumours, and recommended management of these syndromes with a discussion of the role of imaging. The review is written for the practising neuro-oncologist and other specialists who care for patients with genetic syndromes affecting the nervous system.
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Robot Music: A Story for Kids with Li-Fraumeni Syndrome and Other Cancer Predispositions. Tellwell Talent, 2019.
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Robot Music: A Story for Kids with Li-Fraumeni Syndrome and Other Cancer Predispositions. Tellwell Talent, 2019.
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8
Portwine, Carol Ann. Identification and characterization of Li-Fraumeni syndrome families: Molecular and in vitro analysis and development of an in vivo model. 2002.
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Barlow, Jason William. Studies of p53 regulated genes in Li-Fraumeni syndrome and analysis of the effects of retinoic acid on pediatric rhabdomyosarcoma cell lines. 2003.
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Santos, Maria, Eric Bouffet, Carolyn Freeman e Mark M. Souweidane. Choroid plexus tumours. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199651870.003.0006.
Testo completoAbstract (sommario):
Choroid plexus tumours are rare, intraventricular, primary central nervous system tumours derived from the choroid plexus epithelium. They occur predominantly in children and are classified based on histological criteria as choroid plexus papilloma, atypical choroid plexus papilloma, and choroid plexus carcinoma. Choroid plexus carcinomas can occur in the context of Li–Fraumeni syndrome, where the TP53 germline mutation predisposes patients to a wide range of neoplasms. Treatment of these tumours is challenging, due to their high vascularity and the young age of the patients. While surgery is the mainstay of treatment of all choroid plexus tumours, the exact role of adjuvant therapy, particularly in choroid plexus carcinoma, is still unclear. For incompletely resected tumours, there is evidence that neoadjuvant chemotherapy can facilitate second-look surgery and reduce the risk of intraoperative bleeding. However, the role of adjuvant radiation after complete resection remains unclear.
Capitoli di libri sul tema "Syndrome de Li-Fraumeni (LFS)"
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Guerrieri, Patrizia, Paolo Montemaggi, Volker Budach, Carmen Stromberger, Volker Budach, Volker Budach, Anthony E. Dragun et al. "Li-Fraumeni Syndrome". In Encyclopedia of Radiation Oncology, 437. Berlin, Heidelberg: Springer Berlin Heidelberg, 2013. http://dx.doi.org/10.1007/978-3-540-85516-3_405.
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2
Hodgson, Anjelica, Sara Pakbaz e Ozgur Mete. "Li-Fraumeni Syndrome". In Encyclopedia of Pathology, 1–3. Cham: Springer International Publishing, 2020. http://dx.doi.org/10.1007/978-3-319-28845-1_5222-1.
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de Leon, M. Ponz. "Li-Fraumeni Syndrome". In Familial and Hereditary Tumors, 275–86. Berlin, Heidelberg: Springer Berlin Heidelberg, 1994. http://dx.doi.org/10.1007/978-3-642-85076-9_18.
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4
Olivier, Magali, e Pierre Hainaut. "Li-Fraumeni Syndrome". In Encyclopedia of Cancer, 1–7. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27841-9_3345-3.
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Malkin, David. "Li–Fraumeni Syndrome". In Adrenocortical Carcinoma, 173–91. New York, NY: Springer New York, 2009. http://dx.doi.org/10.1007/978-0-387-77236-3_11.
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Hodgson, Anjelica, Sara Pakbaz e Ozgur Mete. "Li-Fraumeni Syndrome". In Endocrine Pathology, 478–80. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-62345-6_5222.
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Olivier, Magali, e Pierre Hainaut. "Li-Fraumeni Syndrome". In Encyclopedia of Cancer, 2486–92. Berlin, Heidelberg: Springer Berlin Heidelberg, 2017. http://dx.doi.org/10.1007/978-3-662-46875-3_3345.
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Olivier, Magali, e Pierre Hainaut. "Li-Fraumeni Syndrome". In Encyclopedia of Cancer, 2035–39. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-16483-5_3345.
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Liu, Dongyou. "Li-Fraumeni Syndrome". In Tumors and Cancers, 49–54. Boca Raton : Taylor & Francis, a CRC title, part of the Taylor & Francis imprint, a member of the Taylor & Francis Group, the academic division of T&F Informa plc, 2018. | Series: Pocket guides to biomedical sciences: CRC Press, 2017. http://dx.doi.org/10.1201/9781315120546-9.
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Villani, Anita, Thierry Frebourg e David Malkin. "Li-Fraumeni Syndrome". In The Hereditary Basis of Childhood Cancer, 1–21. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-74448-9_1.
Testo completoAtti di convegni sul tema "Syndrome de Li-Fraumeni (LFS)"
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Nobrega, Gabriela Bezerra, Marina Bellatti Küller, Gabriela Marçal Rios, Jonathan Yugo Maesaka e José Roberto Filassi. "Follow-up of a Li-Fraumeni syndrome case". In Brazilian Breast Cancer Symposium 2023. Mastology, 2023. http://dx.doi.org/10.29289/259453942023v33s1062.
Testo completoAbstract (sommario):
Introduction: Li-Fraumeni syndrome (LFS) is responsible for about 1% of hereditary breast cancers (BC). We present a case report of a young woman with synchronous osteosarcoma and BC. Case Report: NOB, 23 years old. Mother died with BC at 36 years old and sister died due to neuroblastoma at 2 years old. She was referred in 2021 for a nodule in her left breast and the ultrasound results showed an irregular nodule of 1.5×1.2×1.3 cm BI-RADS®5 and anatomopathological invasive carcinoma of non-special histological type (NST), estrogen receptor 80%, progesterone receptor 100%, Her2 negative, and Ki67 60% cT1N0. It was associated with a lesion in the alveolar mucosa with bleeding and deformity of the oral cavity with anatomopathological high histological osteosarcoma-T1N0. Surgical treatment was performed: maxillectomy of meso and bilateral infrastructure+tracheostomy+reconstruction with microsurgical flap of the fibula and, then, left adenomastectomy+sentinel lymph node biopsy+prosthesis reconstruction. Surgical anatomopathological results in central/medullary high-grade conventional osteosarcoma chondroblasts 7.3×6.1×3.9 cm, free surgical margins and four cervical lymph nodes free of neoplastic involvement, and invasive breast carcinoma NST with medullary characteristics 1.8×1.3 cm, free margins, and absence of metastasis in two sentinel lymph nodes –pT1pN0. Genetic test resulted in pathogenic mutation TP53 gene, position chr17:7.674.257, consequence p.Tyr236HisENST00000269305. Adjuvant chemotherapy was docetaxel+cyclophosphamide. Two years after treatment, she is taking tamoxifen, scheduled for contralateral adenomastectomy, and maintains high-risk follow-up. There is no signal of any cancer disease. Discussion: LFS is an autosomal dominant inheritance of high penetrance. The diagnosis is based on the identification of a pathogenic variant in the TP53 gene. It is related to several tumors diagnosed at an early age. BC is the most common cancer and affects 27–31% of patients. Osteosarcoma corresponds to 3%–16% of cases, usually occurring before the age of 30 years. The prognosis of patients does not differ from those with sporadic cancer. They must be monitored by a multidisciplinary team, screening with annual whole body/breast MRI and mammography, and colonoscopy every 5 years. Genetic counseling is essential.
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Walcott, Farzana Lukmanji, Paul M. Hwang, Ping-yuan Wang, Sharon A. Savage, Phuong Mai, Seth M. Steinberg, Michael N. Pollak, Christina Annunziata e Antonio T. Fojo. "Abstract CT156: Safety and tolerability of metformin for chemoprevention in Li-Fraumeni syndrome (LFS)". In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-ct156.
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Walcott, Farzana L., Paul M. Hwang, Ping-yuan Wang, Sharon A. Savage, Phuong Mai, Seth M. Steinberg, Michael N. Pollak, Philip A. Dennis e Antonio Tito Fojo. "Abstract 29: Design of a phase I chemoprevention study of metformin and Li-Fraumeni syndrome (LFS)". In Abstracts: AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; January 29-February 1, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.cansusc14-29.
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Nees, J., S. Kiermeier, I. Maatouk e S. Schott. "ADDRESS LFS Psychosoziale Versorgung von Li Fraumeni Syndrom Betroffenen und deren Angehörigen". In Kongressabstracts zur Tagung 2020 der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG). © 2020. Thieme. All rights reserved., 2020. http://dx.doi.org/10.1055/s-0040-1718165.
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Lacerda, Elisângela de Paula Silveira, Rebeca Mota Goveia, Paula Francinete Faustino Silva, Thais Bonfim Teixeira e Ruffo de Freitas-Junior. "HEREDITARY BREAST AND OVARIAN CANCER PATIENTS HAVE A FAMILY HISTORY OF CANCER OUTSIDE THE SPECTRUM OF THE SYNDROME, MIMICKING LYNCH AND LI–FRAUMENI SYNDROMES". In Abstracts from the Brazilian Breast Cancer Symposium - BBCS 2021. Mastology, 2021. http://dx.doi.org/10.29289/259453942021v31s2030.
Testo completoAbstract (sommario):
Patients with pathogenic variants (PV) in the BRCA1 and BRCA2 genes have hereditary breast and ovarian cancer syndrome (HBOC). Some patients with HBOC have a family history (FH) of different types of cancer not related to the syndrome. The objective of this study was to observe the FH profile of cancer in patients with HBOC syndrome. A total of 123 patients treated at the Advanced Breast Diagnostic Center (CORA) with clinical criteria suggestive of HBOC syndrome were selected according to the National Comprehensive Cancer Network (NCCN). The collection of 4 ml of blood was performed, which was subjected to DNA extraction and PV analysis in the BRCA1 and BRCA2 genes by next generation sequencing. The data were analyzed using the Sophia DDM and Ion Reporter software. The variants were considered to be pathogenic according to the ACMG criteria. It was found that among 123 patients analyzed, 19 had HBOC syndrome, of whom 5 were related. Thus, we had 16 families with HBOC syndrome. Among the 16 families, 14 (87.5%) had FH from cancers related to HBOC syndrome, 9 (56.25%) had FH from cancers not related to HBOC syndrome, and 1 (16.25%) did not have FH cancer. A total of 8 (50%) of families with HBOC also met the NCCN criteria for other hereditary cancer syndromes, 3 (18.75%) for Li–Fraumeni syndrome (LFS) and HBOC, 3 (18.75%) for Lynch syndrome (LS) and HBOC, and 2 (12.5%) for HBOC, LFS, and LS. The most common cancers observed outside the common spectrum of HBOC syndrome in families were stomach cancer (25%), intestine (18.75%), liver (18.75%), and skin (18.75%). These data suggest the importance of a complete assessment of FH in patients with HBOC syndrome to better understand its relationship with the predisposition to different types of cancer.
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Veiga, Késsila Macedo, Rebeca Mota Goveia, Paula Francinete Faustino da Silva, Adelaide Fernandes Costa e Elisangela de Paula Silveira Lacerda. "Variant analysis in the TP53 gene for families in the state of Goiás with suspected Li-Fraumeni syndrome: tool for early diagnosis and prevention of breast cancer". In Brazilian Breast Cancer Symposium 2024, 25. Mastology, 2024. http://dx.doi.org/10.29289/259453942024v34s1025.
Testo completoAbstract (sommario):
Objective: Breast cancer is the most common type of cancer in the world. In Brazil, there is a high incidence of Li-Fraumeni syndrome (LFS), one of the main syndromes related to the development of hereditary breast cancer. This study aimed to identify the prevalence of variants in the TP53 gene in probands suspected of having LFS and their families. Methodology: We evaluated 123 patients who met the National Comprehensive Cancer Networking criteria for suspected hereditary breast cancer syndromes, who were referred to the Center for Human Genetics/Universidade Federal de Goiás (UFG) by Hospital das Clínicas/UFG. After applying the Informed Consent Form, 4 mL of venous blood was collected for DNA extraction used for next-generation sequencing and analysis of the entire coding region of the TP53 gene. The DNA library was prepared using the PCR target amplification method with the Oncomine™ BRCA Expanded panel kit and subjected to sequencing on the Ion Torrent platform. Raw data were evaluated on the Ion Reporter platform, and variants were classified according to the American College of Medical Genetics. Results: Of the 123 patients evaluated, 12.19% (15/123) were positive for TP53 variants in seven different families. Variants c.1010 G>A (6/7) and c.455C>T (1/7) were identified. Within the families with variants, it was analyzed that 47.05% (8/17) of the family members tested were also positive cases, with 100% (17/17) not developing any type of cancer to date. Conclusion: These data alert to the considerable incidence of LFS in the state of Goiás and draw attention to the power of directing treatment and prevention of breast cancer that genetic tests could provide for our population, with the possibility of personalization monitoring high-risk families.
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Nees, J., S. Kiermeier, I. Maatouk e S. Schott. "ADDress LFS- Studie: Erfassung und Optimierung der psychosozialen Versorgung von Personen mit Li-Fraumeni-Syndrom und deren Angehörigen". In 40. Jahrestagung der Deutschen Gesellschaft für Senologie e.V. © Georg Thieme Verlag KG, 2020. http://dx.doi.org/10.1055/s-0040-1710656.
Testo completo
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Nees, J., S. Kiermeier, I. Maatouk e S. Schott. "ADDress LFS- Studie: Erfassung und Optimierung der psychosozialen Versorgung von Personen mit Li-Fraumeni-Syndrom und deren Angehörigen". In 40. Jahrestagung der Deutschen Gesellschaft für Senologie e.V. © Georg Thieme Verlag KG, 2020. http://dx.doi.org/10.1055/s-0040-1714597.
Testo completo
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Silva, Paula Francinete Faustino da, Rebeca Mota Goveia, Thais Bomfim Teixeira, Bruno Faulin Gamba, Aliny Pereira de Lima, Sílvia Regina Rogatto, Ruffo de Freitas Júnior e Elisângela de Paula Silveira-Lacerda. "EARLY-ONSET BREAST CANCER PATIENTS FULFILLING HEREDITARY BREAST AND OVARY CANCER AND LI-FRAUMENI-LIKE SYNDROMES CAN HARBOR TP53 PATHOGENIC VARIANTS". In Brazilian Breast Cancer Symposium 2022. Mastology, 2022. http://dx.doi.org/10.29289/259453942022v32s2018.
Testo completoAbstract (sommario):
Objective: We investigate the prevalence of TP53 germline pathogenic variants in a cohort of 83 breast cancer patients and 217 family members from the Midwest Brazilian region. Methods: All patients met the clinical criteria for hereditary breast and ovarian cancer syndrome (HBOC) and were negative for BRCA1 and BRCA2 mutations. Moreover, 40 index patients fulfilled HBOC and the Li-Fraumeni-like syndromes (LFL) criteria. The samples were tested using next-generation sequencing for TP53. Results: Three patients harbored TP53 missense pathogenic variants (p.Arg248Gln, p.Arg337His, and p.Arg337Cys), confirmed by Sanger sequencing. One patient showed a large TP53 deletion (exons 2–11), which was also confirmed. The p.R337H variant was detected in only one patient. Conclusion: This study concluded that 4 out of 83 HBOC and LFL patients presented TP53 pathogenic variants at a young age. In contrast to other Brazilian regions, the TP53 p.R337H variant appeared with low prevalence.
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Küller, Marina Bellatti, Gabriela Marçal Rios, Gabriela Bezerra Nobrega, Jonathan Yugo Maesaka e Jose Roberto Filassi. "LI-FRAUMENI SYNDROME: A CASE REPOR". In XXIV Congresso Brasileiro de Mastologia. Mastology, 2022. http://dx.doi.org/10.29289/259453942022v32s1051.
Testo completoAbstract (sommario):
Li-Fraumeni syndrome is a disease with an autosomal dominant inheritance of high penetrance and was originally described in 1969. The definitive diagnosis is based on the identification of a pathogenic variant in the TP53 gene. Birch and Chompret and classical models were used as the clinical criteria to identify individuals who are the candidates for molecular screening. It is responsible for about 1% of hereditary breast cancers and is related to other neoplasms, the most common sarcomas, leukemias, and adrenal carcinoma. Among the differential diagnoses, we can consider pathogenic variants of BRCA1/BRCA2 and Lynch syndrome. The behavior of cancer is usually similar to that of patients without Li-Fraumeni syndrome except for the age of early onset. Screening for the breast cancer with an annual magnetic resonance is recommended in women from the age of 20, colon cancer with colonoscopy every 2 or 5 years from the age of 25, and osteosarcoma and soft-tissue tumor with full-body resonance at an early age. Interventions are recommended for patients with a family history or individuals with a reported mutation. Mastectomy is generally recommended for women with breast cancer due to the risks of a second primary breast cancer or a second radiation-induced cancer. The risk of contralateral breast cancer in patients with TP53 diagnosed under 35 years of age is approximately 4%–7% per year. In this scenario, we bring a case report of a young female patient with synchronous tumors of maxillary osteosarcoma and breast cancer to study the approach, prevention, and guidance in these cases. N.O.B., 21 years old, single, born in São Paulo, nonparturient, mother’s death due to breast cancer at age 36, and sister’s death due to neuroblastoma at age 2. At the first medical appointment in June 2021, she complained of the presence of a nodule in her left breast persisting for 2 years and reported a palate lesion present for 1 month and with rapid growth, associated with existing oral cavity deformity. On the breast ultrasound examination performed in June 2021, a solid, hypoechogenic, irregular, microlobulated, nonparallel to skin was revealed, measuring 1.5×1.2×1.3 cm at 10 h of the left breast (BI-RADS classification®: 5). The pathological report from a directed biopsy of the nodule showed an invasive carcinoma of nonspecial histological type, estrogen receptor 80%, progesterone receptor 100%, Her2 negative, and Ki67 60% — clinical staging cT1N0. The examination of her palate lesions reported high histological osteosarcoma — cT1N0M0. Considering the double-tumor diagnosis plus the highly aggressive lesion of the patient’s palate, the team chooses to start the treatment with partial maxillectomy and bilateral infrastructure surgery, tracheostomy, and reconstruction with a microsurgical flap of the right fibula in July 2021. Later in October 2021, the patient’s treatment was followed by a combination of left adenomastectomy, left sentinel lymph node biopsy, and reconstruction with bilateral prosthesis. Due to family and personal history, she went through genetic testing for pathogenic mutation on the TP53 gene. Fertility preservation was performed with oocyte freezing. As an adjuvant treatment, it is scheduled for four cycles of docetaxel and cyclophosphamide. As prophylactic measures, the patient is expected for an adenectomy in the contralateral breast and to follow up with clinical examinations twice a year, as well as both mammography and MRI once a year.