Journal articles: 'Adenocarcinoma Aneuploidy'

1

Wu, Chuanxin, Jing Zhang, Hua Bao, Ao Wang, Zhuang Luo, Yi Shen, Shuyu Wu, Xue Wu, Yang Shao, and Jianfeng Huang. "Distinct genomic instability landscape of lung adenocarcinoma associated with treatment and metastasis." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 9534. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.9534.

Full text

Abstract:

9534 Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC). Genomic instability, defined as genome-wide copy number alterations, is a key pathogenic signature which occurs at the early stage of most cancers and is associated with an increased risk of recurrence or death. We examined the pattern of genomic instability in primary and metastatic LUAD. Methods: We performed deep targeted sequencing (425 genes) of 3395 tissue samples and whole exome sequencing (WES) of 60 tissue samples from LUAD patients. Whole-genome doubling (WGD) and arm level aneuploidy were analyzed to uncover correlation with clinical phenotypes and other genomic alterations including driver mutations, tumor mutation burden (TMB), and microsatellite instability (MSI). Results: Overall, targeted sequencing revealed that WGD occurred in 64.33% LUAD samples, which was comparable with WES results. Compared to primary site, metastasis exhibited higher proportion of WGD (1.14 fold). Specifically, liver metastasis has the highest WGD percentage among metastasis sites (~87.5%; 1.40 fold increase compared to primary). Interestingly, patients who received tyrosine kinase inhibitors (TKI) had higher frequency of WGD than patients without TKI treatment. In addition, TMB was higher in WGD+ patients but MSI status was not significantly different between groups. Arm-level aneuploidy was prevalent in this cohort. The most common amplification events were 7p gain (62%), 5p gain (54%), and 8q gain (53%); top deletion events were 19p loss (47%), 15q loss (42%), and 10 q loss (41%). Patients with EGFR or TP53 mutation were more likely to have aneuploidy compared to wildtypes. Subgroup analysis showed distinct patterns of aneuploidy among metastasis sites, suggesting organ-specific alterations. Evolution analysis showed 7p gain was an early event common in primary tumor whereas metastatic tumor had multiple distinct evolutionary trajectories following 7p gain. Several copy number signatures were associated with specific TKI and chemotherapies. For example, TKI-naïve tumors lacked 7p gain but had 19p loss as the most common alteration. Conclusions: The genomic landscape of LUAD was characterized by widespread large-scale copy number alterations including WGD and chromosomal aneuploidy. Metastasis had elevated level of aneuploidy compared to primary tumors which were specific to metastatic site. Copy number signature associated with different treatments may contribute to distinct long-term survival and side effects among patients.

APA, Harvard, Vancouver, ISO, and other styles

2

Lin, Jen-Kou, Shih-Ching Chang, Ya-Chien Yang, and Anna Fen-Yau Li. "Loss of Heterozygosity and DNA Aneuploidy in Colorectal Adenocarcinoma." Annals of Surgical Oncology 10, no. 9 (January 2003): 1086–94. http://dx.doi.org/10.1245/aso.2003.12.014.

Full text

APA, Harvard, Vancouver, ISO, and other styles

3

Williams, L. J., D. L. Guernsey, and A. G. Casson. "Biomarkers in the Molecular Pathogenesis of Esophageal (Barrett) Adenocarcinoma." Current Oncology 13, no. 1 (February 1, 2006): 33–43. http://dx.doi.org/10.3747/co.v13i1.76.

Full text

Abstract:

Since the early 1970s, a dramatic change has occurred in the epidemiology of esophageal malignancy in both North America and Europe: the incidence of adenocarcinomas of the lower esophagus and esophagogastric junction is increasing. Several lifestyle factors are implicated in this change, including gastroesophageal reflux disease (gerd). Primary esophageal adenocarcinomas are thought to arise from Barrett esophagus, an acquired condition in which the normal esophageal squamous epithelium is replaced by a specialized metaplastic columnar-cell-lined epithelium. Today, gerd is recognized as an important risk factor in Barrett esophagus. Progression of Barrett esophagus to invasive adenocarcinoma is reflected histologically by the metaplasia–dysplasia–carcinoma sequence. Although several molecular alterations associated with progression of Barrett esophagus to invasive adenocarcinoma have been identified, relatively few will ultimately have clinical application. Currently, the histologic finding of high-grade dysplasia remains the most reliable predictor of progression to invasive esophageal adenocarcinoma. However other promising molecular biomarkers include aneuploidy; 17p loss of heterozygosity, which implicates the TP53 tumour suppressor gene; cyclin D1 protein overexpression; and p16 alterations. It is anticipated that models incorporating combinations of objective scores of sociodemographic and lifestyle risk factors (that is, age, sex, body mass index), severity of gerd, endoscopic and histologic findings, and a panel of biomarkers will be developed to better identify patients with Barrett esophagus at increased risk for malignant progression, leading to more rational endoscopic surveillance and screening programs.

APA, Harvard, Vancouver, ISO, and other styles

4

Gao, Beili, Fujun Yang, Ming Han, Hua Bao, Yi Shen, Ran Cao, Xue Wu, Yang Shao, Changhong Liu, and Zhe Zhang. "Genomic landscape and evolution of arm aneuploidy in lung adenocarcinoma." Neoplasia 23, no. 9 (September 2021): 870–78. http://dx.doi.org/10.1016/j.neo.2021.06.003.

Full text

APA, Harvard, Vancouver, ISO, and other styles

5

Davison, Jon M., J. Michael Krill-Burger, Melissa K. Yee, Tyler J. Foxwell, Maureen A. Lyons-Weiler, James D. Luketich, Katie S. Nason, George K. Michalopoulos, and William A. LaFramboise. "The degree of segmental aneuploidy measured by total copy number abnormalities to predict survival and recurrence in superficial gastroesophageal adenocarcinoma." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): 62. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.62.

Full text

Abstract:

62 Background: Prognostic biomarkers are needed for superficial gastroesophageal adenocarcinoma (EAC) to predict clinical outcomes and select therapy. Although recurrent mutations have been characterized in EAC, little is known about their clinical and prognostic significance. Aneuploidy is predictive of clinical outcome in many malignancies but has not been evaluated in superficial EAC. SNP arrays offer the opportunity to evaluate segmental aneuploidy at high resolution throughout the genome. Methods: We quantified copy number changes in 41 superficial EAC using Affymetrix SNP 6.0 arrays. We identified recurrent chromosomal gains and losses and calculated the total copy number abnormality (CNA) count for each tumor as a measure of aneuploidy. We correlated CNA count with overall survival and time to first recurrence in univariate and multivariate analyses. Results: Recurrent segmental gains and losses involved multiple genes, including: HER2, EGFR, MET, CDK6 , KRAS (recurrent gains); and FHIT, WWOX, CDKN2A/B, SMAD4, RUNX1 (recurrent losses). There was a 40-fold variation in CNA count across all cases. Tumors with the lowest and highest quartile CNA count had significantly better overall survival (p=0.032, log rank test) and time to first recurrence (p=0.010, log rank test) compared to those with intermediate CNA counts. In multivariate Cox analysis, there was a 3.4-fold (95% CI, 1.1–10.4) increased hazard of death among cases with intermediate CNA counts after adjusting for other predictors of survival (N stage, angiolymphatic invasion and tumor size). Similarly, there was a 7.3-fold (95% CI, 1.5-34) increased risk of recurrence for these patients. Conclusions: SNP arrays facilitate the assessment of recurrent chromosomal gain and loss and allow high resolution, quantitative assessment of segmental aneuploidy (total CNA count).The non-monotonic association of segmental aneuploidy with survival has been described in other tumors such as breast and ovarian carcinoma. The degree of segmental aneuploidy is a promising prognostic biomarker in a potentially curable form of EAC.

APA, Harvard, Vancouver, ISO, and other styles

6

Viganó, Cristina, Conrad von Schubert, Erik Ahrné, Alexander Schmidt, Thomas Lorber, Lukas Bubendorf, Judith R. F. De Vetter, Guido J. R. Zaman, Zuzana Storchova, and Erich A. Nigg. "Quantitative proteomic and phosphoproteomic comparison of human colon cancer DLD-1 cells differing in ploidy and chromosome stability." Molecular Biology of the Cell 29, no. 9 (May 2018): 1031–47. http://dx.doi.org/10.1091/mbc.e17-10-0577.

Full text

Abstract:

Although aneuploidy is poorly tolerated during embryogenesis, aneuploidy and whole chromosomal instability (CIN) are common hallmarks of cancer, raising the question of how cancer cells can thrive in spite of chromosome aberrations. Here we present a comprehensive and quantitative proteomics analysis of isogenic DLD-1 colorectal adenocarcinoma cells lines, aimed at identifying cellular responses to changes in ploidy and/or CIN. Specifically, we compared diploid (2N) and tetraploid (4N) cells with posttetraploid aneuploid (PTA) clones and engineered trisomic clones. Our study provides a comparative data set on the proteomes and phosphoproteomes of the above cell lines, comprising several thousand proteins and phosphopeptides. In comparison to the parental 2N line, we observed changes in proteins associated with stress responses and with interferon signaling. Although we did not detect a conspicuous protein signature associated with CIN, we observed many changes in phosphopeptides that relate to fundamental cellular processes, including mitotic progression and spindle function. Most importantly, we found that most changes detectable in PTA cells were already present in the 4N progenitor line. This suggests that activation of mitotic pathways through hyper-phosphorylation likely constitutes an important response to chromosomal burden. In line with this conclusion, cells with extensive chromosome gains showed differential sensitivity toward a number of inhibitors targeting cell cycle kinases, suggesting that the efficacy of anti-mitotic drugs may depend on the karyotype of cancer cells.

APA, Harvard, Vancouver, ISO, and other styles

7

Tsiambas, E., D. Alexopoulou, S. Lambropoulou, K. Gerontopoulos, P. Karakitsos, and A. Karameris. "Targeting topoisomerase IIa in endometrial adenocarcinoma." International Journal of Gynecologic Cancer 16, no. 3 (2006): 1424–31. http://dx.doi.org/10.1136/ijgc-00009577-200605000-00073.

Full text

Abstract:

Topoisomerase IIa is a nucleic enzyme that affects the topological structure of DNA and also is a target for chemotherapy (ie, anthracyclines). In this study, we coevaluated its protein expression with chromosome 17 and gene status. Using tissue microarrays, 40 cases of sporadic, primary endometrial adenocarcinomas, 5 cases of atypical hyperplasia, and 5 cases of benign hyperplasia were obtained and reembedded into two paraffin blocks with a core diameter of 1 mm. Immunohistochemistry combined with chromogenic in situ hybridization was performed in 2 and 5 μm sections, respectively. Finally using a semiautomated Image Analysis System, we evaluated the levels of Nuclear labeling index of topoisomerase IIa expression. Statistical analysis was performed by SPSS version 11.0 software. The results indicate that chromosome 17 instability (aneuploidy in 7/40 cases) and Topo IIa gene deregulation (amplification in 3/40 and deletion in 1/40 cases) are significant genetic events correlated with biologic behavior in endometrial adenocarcinoma. Because protein overexpression was observed in a significant proportion of the tumors (18/40), detection of the specific gene deregulation mechanism is a crucial process for application of targeted chemotherapies, which are characterized by different levels of cardiotoxicity and other serious effects.

APA, Harvard, Vancouver, ISO, and other styles

8

Nanus, D. M., D. P. Kelsen, D. Niedzwiecki, D. Chapman, M. Brennan, E. Cheng, and M. Melamed. "Flow cytometry as a predictive indicator in patients with operable gastric cancer." Journal of Clinical Oncology 7, no. 8 (August 1989): 1105–12. http://dx.doi.org/10.1200/jco.1989.7.8.1105.

Full text

Abstract:

Adenocarcinoma of the proximal portion of the stomach (gastroesophageal [GE] junction and cardia) is increasing in incidence. The inferior survival of patients with GE-cardia lesions as compared with patients with tumors located in the body and antrum has been attributed to anatomic features. To determine if a biological difference could explain the varying prognosis, flow cytometric studies were performed prospectively in 50 patients with operable gastric cancer and analyzed for association with site, histology, gender, age, stage, and disease-free survival. DNA aneuploidy significantly correlated with tumor location: 96% of GE-cardia carcinomas were aneuploid as compared with 48% of body-antrum tumors (P = .0008). Nodal involvement was more common in aneuploid tumors (P = .0548), and women were more likely to have diploid tumors than were men (P = .0233). The median disease-free survival for patients with diploid tumors was 18.5 months as compared with 5.4 months for patients with aneuploid carcinomas (P = .076). Furthermore, within the body-antrum of the stomach, patients with diploid tumors had a significantly better disease-free survival than did those with aneuploid tumors from the same site (18.4 v 4.7 months, P = .0185). These results indicate there is a difference in the DNA content of gastric tumors located in different sites within the stomach and that DNA content correlates with prognosis.

APA, Harvard, Vancouver, ISO, and other styles

9

Makiyama, Kazuya, Masaki Tokunaga, Minoru Itsuno, Walter Zea-Iriarte, Kohei Hara, and Tohru Nakagoe. "DNA aneuploidy in a case of rectosigmoid adenocarcinoma complicated by ulcerative colitis." Journal of Gastroenterology 30, no. 2 (April 1995): 258–63. http://dx.doi.org/10.1007/bf02348675.

Full text

APA, Harvard, Vancouver, ISO, and other styles

10

Maley, Carlo C., and Anil K. Rustgi. "Barrett's Esophagus and Its Progression to Adenocarcinoma." Journal of the National Comprehensive Cancer Network 4, no. 4 (April 2006): 367–74. http://dx.doi.org/10.6004/jnccn.2006.0031.

Full text

Abstract:

Barrett's esophagus (BE) is the only known precursor for esophageal adenocarcinoma (EA). Therefore, the presence of BE identifies a high-risk group of patients who may be followed-up for early detection of EA and treated to reduce the risk for its progression. The initiating event for BE is unknown, although it is associated with chronic gastric reflux. Many of the genetic lesions involved in BE neoplastic progression are known, including loss of CDKN2A (p16) and TP53 (p53) and the development of tetraploidy and aneuploidy. Intensive endoscopic surveillance has been shown to improve survival although it can be difficult to implement in practice. Several exposures may be altered to reduce the risk for progression, including weight, diet, and the use of nonsteroidal anti-inflammatory drugs. However, most of these results should be confirmed in additional cohorts before they are used to change clinical practice.

APA, Harvard, Vancouver, ISO, and other styles

11

Campomenosi, Paola, Paola Assereto, Massimo Bogliolo, Gilberto Fronza, Angelo Abbondandolo, Antonella Capasso, Patrizia F. Bellomo, et al. "p53 Mutations and DNA Ploidy in Colorectal Adenocarcinomas." Analytical Cellular Pathology 17, no. 1 (1998): 1–12. http://dx.doi.org/10.1155/1998/396371.

Full text

Abstract:

The p53 tumour suppressor gene has an important role in the the maintenance of genome stability and its mutational inactivation may be at the origin of aneuploidy in cancer cells. The aim of this study was to determine whether p53 mutations were associated to DNA aneuploidy, as assessed by flow cytometry, in colorectal adenocarcinomas. Analysis of p53 mutations spectrum of the sorted nuclei was done by Denaturing Gradient Gel Electrophoresis (DGGE) and DNA sequencing. Overall, we studied 20 adenocarcinomas, the corresponding control mucosa, and 7 lymph node metastases.Five tumours (25%) were DNA diploid, while 15 tumours (75%) were composed of DNA aneuploid and diploid subpopulations. DNA diploid control mucosa and adenocarcinomas showed no p53 mutations, while 60% of the tumours with DNA aneuploidy had p53 mutations. Therefore, p53 mutations occurred significantly more often in DNA aneuploid than in DNA diploid tumours (p< 0.04, Fisher’s exact test). Incidences of DNA aneuploidy and p53 mutations in lymph node metastases were 60 and 86%, respectively. In all tumours showing a p53 mutation, the wild-type allele was not or only bearly visible in DNA aneuploid cells suggesting that, in such cells, aneuploidy is accompanied by complete p53 functional inactivation.The present observations suggest that p53 mutations may have a role in the origin of aneuploidy at late stages of colorectal carcinogenesis.

APA, Harvard, Vancouver, ISO, and other styles

12

Dunn, Jason M., Stuart A. McDonald, Dahmane Oukrif, Rehan J. Haidry, Mohammed A. Butt, Laurence Lovat, Gareth H. Williams, and Marco Novelli. "Plk-1 is Upregulated in Barrett's Adenocarcinoma and is a Surrogate Marker of Aneuploidy." Gastroenterology 140, no. 5 (May 2011): S—667. http://dx.doi.org/10.1016/s0016-5085(11)62767-4.

Full text

APA, Harvard, Vancouver, ISO, and other styles

13

Dunn, J. M., S. A. McDonald, D. Oukrif, R. J. Haidry, M. A. Butt, E. Lovat, L. B. Lovat, G. H. Williams, and M. R. Novelli. "PLK-1 is upregulated in barrett's adenocarcinoma and is a surrogate marker of aneuploidy." Gut 60, Suppl 1 (March 13, 2011): A172. http://dx.doi.org/10.1136/gut.2011.239301.366.

Full text

APA, Harvard, Vancouver, ISO, and other styles

14

Steilen, H., R. Ketter, K. Romanakis, T. Zwergel, G. Unteregger, H. Bonkhoff, G. Seitz, M. Ziegler, K. D. Zang, and B. Wullich. "DNA aneuploidy in prostatic adenocarcinoma: A frequent event as shown by fluorescence in situ DNA hybridization." Human Pathology 25, no. 12 (December 1994): 1306–13. http://dx.doi.org/10.1016/0046-8177(94)90090-6.

Full text

APA, Harvard, Vancouver, ISO, and other styles

15

Costa Guimarães, A., L. Gonçalves Quintana, M. Ferreira Leal, S. Satomi Takeno, P. Pimentel Assumpção, E. Moura Lima, A. Salim Khayat, E. Suchi Chen, M. de Arruda Cardoso Smith, and R. Rodríguez Burbano. "Aneuploidy of chromosome 8 detected by fluorescence in situ hybridisation in ACP01 cell line gastric adenocarcinoma." Clinical and Experimental Medicine 6, no. 3 (October 2006): 129–33. http://dx.doi.org/10.1007/s10238-006-0108-5.

Full text

APA, Harvard, Vancouver, ISO, and other styles

16

Dabrowski, Dominik, Roberto F. Silva, Michael Constantinescu, Rodney E. Shackelford, Nestor Dela Cruz, and Eric X. Wei. "Synchronous Occurrence of Splenic Pleomorphic Mantle Cell Lymphoma and Esophageal Adenocarcinoma with Overexpression of BCL1 Protein." Case Reports in Oncological Medicine 2020 (December 21, 2020): 1–7. http://dx.doi.org/10.1155/2020/8888829.

Full text

Abstract:

Synchronous occurrences of mantle cell lymphoma (MCL), or intermediate lymphocytic lymphoma, and other malignancies are rare. Such cases present diagnostic and especially therapeutic challenges, making them of particular interest to study. We report a case of synchronic MCL and an esophageal tumor in an elderly male patient. Morphologically, the tumors were classified as splenic pleomorphic MCL and adenocarcinoma of the esophagus occurring concurrently. The pleomorphic MCL mimicked diffuse large B cell lymphoma (DLBCL) but lacked larger centroblast- or immunoblast-like cells. Curiously, both tumors overexpressed cyclin D1 by immunohistochemistry. This is an important feature that distinguishes MCL pathologically from two of its closest entities in the differential diagnosis: chronic lymphocytic leukemia and DLBCL, the latter of which mantle cells cannot transform into. The lymphoproliferation revealed IGH/CCND1 translocation by FISH, but the esophageal adenocarcinoma only showed CCND1 aneuploidy without break-apart signals. Since the gastrointestinal (GI) tract is a common site of extranodal involvement by MCL and lymphomatous polyposis can present as GI polyps, adequate care was taken to differentiate the esophageal adenocarcinoma from advanced stagings of MCL, as well as metastatic adenocarcinoma. Despite numerous immunohistochemical stainings studied, only BCL1 was demonstrated to have partial overlap in both tumors. The patient underwent esophagectomy and splenectomy. A subsequent metastatic primary lung squamous cell carcinoma was diagnosed, after which the patient expired. MCL typically presents at an advanced stage and has been deemed incurable with a prognosis of only several years. It is unclear whether the patient succumbed to complications of his MCL or the metastatic squamous cell carcinoma. Furthermore, he was lost to follow-up for a year and only received treatment after his third cancer was diagnosed. We have reviewed previous reports of synchronic mantle cell lymphoma and other solid tumors or hematological malignancies in the literature.

APA, Harvard, Vancouver, ISO, and other styles

17

Calcagno, Danielle Queiroz. "Interrelationship between chromosome 8 aneuploidy,C-MYCamplification and increased expression in individuals from northern Brazil with gastric adenocarcinoma." World Journal of Gastroenterology 12, no. 38 (2006): 6207. http://dx.doi.org/10.3748/wjg.v12.i38.6207.

Full text

APA, Harvard, Vancouver, ISO, and other styles

18

Davison, Jon M., Melissa Yee, J. Michael Krill-Burger, Maureen A. Lyons-Weiler, Lori A. Kelly, Christin M. Sciulli, Katie S. Nason, James D. Luketich, George K. Michalopoulos, and William A. LaFramboise. "The Degree of Segmental Aneuploidy Measured by Total Copy Number Abnormalities Predicts Survival and Recurrence in Superficial Gastroesophageal Adenocarcinoma." PLoS ONE 9, no. 1 (January 16, 2014): e79079. http://dx.doi.org/10.1371/journal.pone.0079079.

Full text

APA, Harvard, Vancouver, ISO, and other styles

19

Mackenzie, Gary, D. Oukrif, M. Novelli, S. Green, S. Bown, and L. Lovat. "The Presence of Aneuploidy Following Photodynamic Therapy for Barrett's Esophagus Predicts Late Relapse to High Grade Dysplasia Or Adenocarcinoma." Gastrointestinal Endoscopy 65, no. 5 (April 2007): AB145. http://dx.doi.org/10.1016/j.gie.2007.03.191.

Full text

APA, Harvard, Vancouver, ISO, and other styles

20

Büyükçelik, Abdullah, Handan Onur, Hakan Akbulut, Bülent Yalçin, Arzu Ensari, Güngör Utkan, Binnur Sönmez Önal, and Fikri İçli. "Expression of P53 Protein and Dna Flow Cytometry in Gastric Adenocarcinoma: Implications in Patients Treated with Adjuvant Etoposide, Adriamycin and Cisplatin." Tumori Journal 91, no. 4 (July 2005): 302–8. http://dx.doi.org/10.1177/030089160509100403.

Full text

Abstract:

Aims and background We evaluated the prognostic value of p53 protein, DNA content and S-phase fraction in patients with adenocarcinoma of the stomach or the gastroesophageal junction treated with adjuvant etoposide, doxorubicin and cisplatin. Methods and study design Thirty-five consecutive patients with stage II or III gastric or gastroesophagial junction adenocarcinoma treated with at least two cycles of adjuvant etoposide, doxorubicin and cisplatin after curative gastric resection were included. The expression of p53 protein was determined by immunohistochemistry and DNA content by flow cytometry. The presence of p53 expression and DNA content was compared with clinicopathological features. Results Median age was 54 years (range, 31–71). P53 expression was detected in 42.9% (15 of 35) of gastric cancer tissues of the patients. Aneuploidy was observed in 31.4% of patients, and S-phase fraction was more than 10% in 22.9%. P53 immunoreactivity (33.3% vs 47.8%) was more common in advanced disease. There was no association among p53 immunoreactivity, DNA content and S-phase fraction. We also found no significant relationship between p53 immunoreactivity, DNA content, S-phase fraction or other clinicopathological parameters. In univariate analysis, the involvement of lymph nodes was a significant predictor of a poor outcome (P = 0.001). Also, p53-positive patients had a poor survival close to the level of significance (P = 0.051). Likewise, p53 immunoreactivity (P = 0.0071), in addition to lymph node involvement (P = 0.0016), were the independent prognostic factors in multivariate analysis. Conclusions This trial supports the results of previous reports that p53 immunoreactivity is a prognostic factor for patients with adenocarcinoma of stomach or gastroesophageal junction treated with adjuvant chemotherapy.

APA, Harvard, Vancouver, ISO, and other styles

21

Yamaguchi, Katsumi, Alisha O. Soares, Loyal A. Goff, Anjali Talasila, Jungbin A. Choi, Daria Ivenitsky, Sadik Karma, et al. "Striking heterogeneity of somatic L1 retrotransposition in single normal and cancerous gastrointestinal cells." Proceedings of the National Academy of Sciences 117, no. 51 (December 4, 2020): 32215–22. http://dx.doi.org/10.1073/pnas.2019450117.

Full text

Abstract:

Somatic LINE-1 (L1) retrotransposition has been detected in early embryos, adult brains, and the gastrointestinal (GI) tract, and many cancers, including epithelial GI tumors. We previously found numerous somatic L1 insertions in paired normal and GI cancerous tissues. Here, using a modified method of single-cell analysis for somatic L1 insertions, we studied adenocarcinomas of colon, pancreas, and stomach, and found a variable number of somatic L1 insertions in tumors of the same type from patient to patient. We detected no somatic L1 insertions in single cells of 5 of 10 tumors studied. In three tumors, aneuploid cells were detected by FACS. In one pancreatic tumor, there were many more L1 insertions in aneuploid than in euploid tumor cells. In one gastric cancer, both aneuploid and euploid cells contained large numbers of likely clonal insertions. However, in a second gastric cancer with aneuploid cells, no somatic L1 insertions were found. We suggest that when the cellular environment is favorable to retrotransposition, aneuploidy predisposes tumor cells to L1 insertions, and retrotransposition may occur at the transition from euploidy to aneuploidy. Seventeen percent of insertions were also present in normal cells, similar to findings in genomic DNA from normal tissues of GI tumor patients. We provide evidence that: 1) The number of L1 insertions in tumors of the same type is highly variable, 2) most somatic L1 insertions in GI cancer tissues are absent from normal tissues, and 3) under certain conditions, somatic L1 retrotransposition exhibits a propensity for occurring in aneuploid cells.

APA, Harvard, Vancouver, ISO, and other styles

22

Guimarães, Adriana Costa, Eleonidas Moura Lima, André Salim Khayat, Mário Henrique Girão Faria, Silvia Helena Barem Rabenhorst, Márcia Valéria Pitombeira, Paulo Pimentel Assumpção, et al. "Interrelationships among chromosome aneuploidy, promoter hypermethylation, and protein expression of the CDKN2A gene in individuals from northern Brazil with gastric adenocarcinoma." Cancer Genetics and Cytogenetics 179, no. 1 (November 2007): 45–51. http://dx.doi.org/10.1016/j.cancergencyto.2007.07.019.

Full text

APA, Harvard, Vancouver, ISO, and other styles

23

Moore, Catherine Elizabeth, Benjamin Darbro, Daniel James Berg, Gerald H. Clamon, Ryan W. Askeland, and Taher Abu Hejleh. "ALK, MET, and HER2 in esophageal adenocarcinoma with signet ring cell morphology." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): 138. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.138.

Full text

Abstract:

138 Background: Signet cell morphology (SCM) is seen in various cancers. In Non-Small Cell Lung Cancer (NSCLC), SCM is associated with ALK gene rearrangements and MET amplification. Crizotinib is an ALK/MET inhibitor that showed dramatic responses in ALK rearranged NSCLC. In this study, we explored ALK rearrangements as well as MET and HER-2 amplification in esophageal carcinoma with SCM. Methods: We reviewed the medical records for 9 patients (pts) seen at the University of Iowa with a diagnosis of esophageal adenocarcinoma and SCM. Clinical characteristics were abstracted. The tumors were tested for ALK rearrangement by fluorescence in situ hybridization (FISH) using the ALK break-apart probe set (Abbott Vysis) and for MET amplification utilizing a MET/CEP7 FISH-probe combination. Both rearrangements and copy number of ALK were assessed as was amplification of MET relative to the centromere signal of chromosome 7. HER-2 was tested by immunohistochemistry (IHC) utilizing the FDA approved DAKO Hercept Test per the ToGA trial methods. Results: Average age at diagnosis was 60 years (43-82). Five pts were males. Neoadjuvant treatment was delivered in 5 of 9 pts. Esophagectomy was done in 7 of 9 pts. Median survival time was 5.8 months (range, 2.4 to 24 months). Histology was consistent with adenocarcinoma in all specimens. No ALK rearrangements were detected. One case had 4-15 extra copies of ALK in 58% of the nuclei. In that same case, there was a relative gain of MET compared to CEP7 (ratio MET/CEP7 = 1.88). Regarding HER-2, 7 of 9 pts were negative (<2+), 1 was equivocal (2+), and one was not done due to lack of tissue. The patient with high copy gain of ALK and a relative copy number increase of MET was treated with Crizotinib on compassionate use basis for 3 weeks after which the treatment was discontinued due to significant progression clinically and radiographically. Conclusions: SCM in esophageal adenocarcinoma was not associated with ALK rearrangements, or increased frequency of MET or HER-2 amplification. Overall, the results were most consistent with copy number variable status of ALK and MET as a result of chromosomal aneuploidy as opposed to locus specific rearrangement or amplification and did not result in significant response to Crizotinib.

APA, Harvard, Vancouver, ISO, and other styles

24

Stoecklein, Nikolas H., Andreas M. Luebke, Andreas Erbersdobler, Wolfram T. Knoefel, Winfried Schraut, Pablo E. Verde, Franziska Stern, et al. "Copy Number of Chromosome 17 but Not HER2 Amplification Predicts Clinical Outcome of Patients With Pancreatic Ductal Adenocarcinoma." Journal of Clinical Oncology 22, no. 23 (December 1, 2004): 4737–45. http://dx.doi.org/10.1200/jco.2004.05.142.

Full text

Abstract:

Purpose To determine the frequency and the potential clinical use of HER2 (17q21) gene amplification and chromosome 17 aneuploidy in pancreatic ductal adenocarcinoma (PDAC). Materials and Methods Serial tissue sections of 50 resected PDACs were analyzed with chromogenic in situ hybridization using locus-specific HER2 probes and centromeric probes for chromosome 17. Centromeric probes for chromosome 7 and 8 were hybridized to confirm ploidy levels. Expression of HER2 protein was assessed by immunohistochemistry. Correlations of experimental findings with clinical and follow-up data were tested. Results The HER2 gene locus was frequently (24%) amplified in PDAC and the rate of overexpression (2+ and 3+) was 10%, but no prognostic significance was found. Copy number analysis of chromosomes 7, 8, and 17 revealed disomic (40%), trisomic (36%), and hypertetrasomic (24%) tumors. Compared with patients with disomic tumors, patients with hypertetrasomic tumors exhibited a significantly decreased relapse-free and overall survival (5.0 v 13.0 months, P = .0144 and 7.0 v 20.0 months, P = .0099, respectively). Multivariate analysis confirmed the independent prognostic significance of hypertetrasomy. Conclusion Tumor ploidy levels correlate with prognosis of PDAC patients, indicating characteristic biologic properties of PDAC with high chromosomal instability. In contrast, no prognostic influence on patient outcome was found for the amplification of the HER2 oncogene or p185HER2 overexpression. Therefore, evaluation of ploidy levels offers new opportunities for patient stratification in clinical trials and enables novel approaches to study the well-known aggressiveness of PDAC.

APA, Harvard, Vancouver, ISO, and other styles

25

Kumaki, Yuichi, Steve Olsen, Mitsukuni Suenaga, Tsuyoshi Nakagawa, Hiroyuki Uetake, and Sadakatsu Ikeda. "Comprehensive Genomic Profiling of Circulating Cell-Free DNA Distinguishes Focal MET Amplification from Aneuploidy in Diverse Advanced Cancers." Current Oncology 28, no. 5 (September 26, 2021): 3717–28. http://dx.doi.org/10.3390/curroncol28050317.

Full text

Abstract:

Amplification (amp) of MET can be observed in cases of focal gene copy number gain, such as MET-driven amp, or with a gain of chromosome 7, such as aneuploidy. Several studies have shown that only high-level focal MET amp (MET/CEP7 ratio ≥5) is oncogenic, with such tumors responding to targeted therapy. However, there are few reports on how to distinguish between focal amplification and aneuploidy using next-generation sequencing (NGS). A total of 1025 patients with advanced solid tumors (typically pre-treated) were tested with a non-invasive comprehensive cfDNA NGS panel (Guardant360) from July 2014 to June 2019. Since bioinformatics upgrades of Guardant360 were undergoing in September 2018, focal MET amp was determined by our independent algorithm using the cohorts tested before September 2018 (291 patients), and validation was performed in the remaining cohort (734 patients). MET alterations (alts) associated with aberrant signaling were found in 110 patients (10.7%) among nine different cancer types, most commonly in non-small cell (12.2%, 62/510) and small cell (33.3%, 3/9) lung cancers, gastroesophageal cancer (19.4%, 7/36), and prostate adenocarcinoma (15.6%; 5/32). Among 291 patients tested before September 2018, 37 (12.7%) had MET alts. Among these, 24 (64.9%) had amps, 5 (13.5%) had exon 14 skipping, and 13 (35.1%) had single nucleotide variants (SNVs). Co-alterations, such as amp + SNVs, were found in four samples (10.8%). Among 24 MET amps, 29.2% (7/24) were focal according to our algorithm. MET copy number was significantly higher with focal amp compared to non-focal amp (mean copy number 3.26 vs. 2.44, respectively, p = 0.00304). In 734 patients tested after September 2018, our definition of focal MET amp was detected in 4.2% (31/734). Overall, focal amplification based on our algorithm was 3.7% (=38/1025). This study describes an approach to distinguish focal and non-focal MET amplification using comprehensive genomic profiling of cfDNA in advanced cancer patients. Focal MET amp accounted for ~30% of all MET amp, which was found in 3.7% of patients with diverse cancers and was associated with a higher plasma copy number. Clinical studies are warranted to assess the clinical utility of targeted therapies for tumors with focal MET amplification detected by NGS of cfDNA.

APA, Harvard, Vancouver, ISO, and other styles

26

Spada, Neal, Jacqueline Birkness, Sanja Dacic, James D. Luketich, Katie Sue Nason, Weijing Sun, and Jon M. Davison. "Association of chromosome 17 copy number instability with favorable prognosis in nonsurgically treated gastroesophageal adenocarinoma and impaired response to trastuzumab." Journal of Clinical Oncology 35, no. 4_suppl (February 1, 2017): 61. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.61.

Full text

Abstract:

61 Background: Chromosomal instability (CIN), defined as cell to cell variation in copy number, is a feature of solid tumors that has been shown in experimental systems to result in aneuploidy, DNA damage, changes in gene expression, and genetically heterogeneous cell populations. In esophageal adenocarcinoma, chromosome 17 (Chr17) aneusomy is associated with heterogeneous HER2 amplification, a marker of poor prognosis (Yoon et al., J Clin Oncol 2012), but the association between CIN, HER2 amplification and clinical outcome has not been well studied. Methods: We retrospectively analyzed individual cell Chr17 centromere counts in 348 gastroesophageal adenocarcinomas that were tested for HER2 amplification. As an estimate of Chr17 CIN (CIN-17), we calculated the percentage of cells with centromere counts differing from the mode (modal centromere deviation, MCD, Roylance et al. Cancer Epidemiol Biomarkers Prev, 2011). We analyzed the association of CIN-17 with Chr17 aneusomy, HER2 amplification, pathologic tumor characteristics and clinical outcome. Results: Using pre-established cutoffs, we found CIN-17 (MCD > 30%) in 45% (158/348) and extreme CIN-17 (MCD > 45%) in 28% (99/348) of cases. Compared to CIN-17 negative tumors, CIN-17 positive tumors were more likely to be polysomic (77% vs 0.5%, P < 0.001) and Lauren intestinal type (84% vs 70%, P = 0.005). HER2 amplification was detected in 23% (80/348) of tumors, but there was no association with CIN-17 (P = 0.493). In patients who received pharmacologic therapy (n = 77), there was a 58% reduction in overall mortality associated with extreme CIN-17 (HR = 0.42, 0.25-0.72) independent of age, stage and addition of trastuzumab. Addition of trastuzumab to pharmacologic therapy showed a trend toward improved clinical outcome only in the subgroup without extreme CIN (n = 50, HR = 0.37, 0.13-1.06). CIN-17 was not associated with differences in patient survival after surgical resection. Conclusions: In this retrospective study, extreme CIN-17 was a favorable prognostic factor in patients who receive chemotherapy but could impair response to trastuzumab. These findings warrant further study.

APA, Harvard, Vancouver, ISO, and other styles

27

Pavlov, Kirill, and Carlo C. Maley. "New models of neoplastic progression in Barrett's oesophagus." Biochemical Society Transactions 38, no. 2 (March 22, 2010): 331–36. http://dx.doi.org/10.1042/bst0380331.

Full text

Abstract:

Research in Barrett's oesophagus, and neoplastic progression to OAC (oesophageal adenocarcinoma), is hobbled by the lack of good pre-clinical models that capture the evolutionary dynamics of Barrett's cell populations. Current models trade off tractability for realism. Computational models are perhaps the most tractable and can be used both to interpret data and to develop intuitions and hypotheses for neoplastic progression. Tissue culture models include squamous cell lines, Barrett's oesophagus cell lines and OAC cell lines, although it was recognized recently that BIC-1, SEG-1 and TE-7 are not true OAC cell lines. Some of the unrealistic aspects of the micro-environment in two-dimensional tissue culture may be overcome with the development of three-dimensional organotypic cultures of Barrett's oesophagus. The most realistic, but least tractable, model is a canine surgical model that generates reflux and leads to an intestinal metaplasia. Alternatively, rat surgical models have gained popularity and should be tested for the common genetic features of Barrett's oesophagus neoplastic progression in humans including loss of CDKN2A (cyclin-dependent kinase inhibitor 2A) and TP53 (tumour protein 53), generation of aneuploidy and realistic levels of genetic diversity. This last feature will be important for studying the effects of cancer-prevention interventions. In order to study the dynamics of progression and the effects of an experimental intervention, there is a need to follow animals longitudinally, with periodic endoscopic biopsies. This is now possible and represents an exciting opportunity for the future.

APA, Harvard, Vancouver, ISO, and other styles

28

Enblad, Malin, Wilhelm Graf, Alexei Terman, Pascal Pucholt, Björn Viklund, Anders Isaksson, and Helgi Birgisson. "Gains of Chromosome 1p and 15q are Associated with Poor Survival After Cytoreductive Surgery and HIPEC for Treating Colorectal Peritoneal Metastases." Annals of Surgical Oncology 26, no. 13 (October 16, 2019): 4835–42. http://dx.doi.org/10.1245/s10434-019-07923-6.

Full text

Abstract:

Abstract Purpose Genetic alterations in colorectal peritoneal metastases (PM) are largely unknown. This study was designed to analyze whole-genome copy number alterations (CNA) in colorectal PM and to identify alterations associated with prognosis after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Methods All patients with PM, originating from a colorectal adenocarcinoma, who were treated with CRS and HIPEC in Uppsala Sweden, between 2004 and 2015, were included (n = 114). DNA derived from formalin-fixed paraffin-embedded (FFPE) specimens were analyzed for CNA using molecular inversion probe arrays. Results There were extensive but varying degrees of CNA, ranging from minimal CNA to total aneuploidy. In particular, gain of parts of chromosome 1p and major parts of 15q were associated with poor survival. A combination of gains of 1p and 15q was associated with poor survival, also after adjustment for differences in peritoneal cancer index and completeness of cytoreduction score [hazard ratio (HR) 5.96; 95% confidence interval (CI) 2.19–16.18]. These patients had a mean copy number (CN) of 3.19 compared with 2.24 in patients without gains. Complete CN analysis was performed in 53 patients. Analysis was unsuccessful for the remaining patients due to insufficient amounts of DNA and signals caused by interstitial components and normal cells. There was no difference in survival between patients with successful and unsuccessful CN analysis. Conclusions This study shows that gains of parts of chromosome 1p and of major parts of chromosome 15q were significantly associated with poor survival after CRS and HIPEC, which could represent future prognostic biomarkers.

APA, Harvard, Vancouver, ISO, and other styles

29

Jones, E. C., J. McNeal, N. Bruchovsky, and G. de Jong. "DNA content in prostatic adenocarcinoma. A flow cytometry study of the predictive value of aneuploidy for tumor volume, percentage gleason grade 4 and 5, and lymph node metastases." Cancer 66, no. 4 (August 15, 1990): 752–57. http://dx.doi.org/10.1002/1097-0142(19900815)66:4<752::aid-cncr2820660426>3.0.co;2-1.

Full text

APA, Harvard, Vancouver, ISO, and other styles

30

Thu, K. L., J. Silvester, M. J. Elliott, W. Ba-alawi, M. H. Duncan, A. C. Elia, A. S. Mer, et al. "Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer." Proceedings of the National Academy of Sciences 115, no. 7 (January 29, 2018): E1570—E1577. http://dx.doi.org/10.1073/pnas.1719577115.

Full text

Abstract:

TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models. CFI-402257 induced apoptosis and potentiated aneuploidy in TNBC lines by accelerating progression through mitosis and inducing mitotic segregation errors. We used genome-wide CRISPR/Cas9 screens in multiple TNBC cell lines to identify mechanisms of resistance to CFI-402257. Our functional genomic screens identified members of the anaphase-promoting complex/cyclosome (APC/C) complex, which promotes mitotic progression following inactivation of the SAC. Several screen candidates were validated to confer resistance to CFI-402257 and other TTKis using CRISPR/Cas9 and siRNA methods. These findings extend the observation that impairment of the APC/C enables cells to tolerate genomic instability caused by SAC inactivation, and support the notion that a measure of APC/C function could predict the response to TTK inhibition. Indeed, an APC/C gene expression signature is significantly associated with CFI-402257 response in breast and lung adenocarcinoma cell line panels. This expression signature, along with somatic alterations in genes involved in mitotic progression, represent potential biomarkers that could be evaluated in ongoing clinical trials of CFI-402257 or other TTKis.

APA, Harvard, Vancouver, ISO, and other styles

31

Blegen, Harald, B. Michael Ghadimi, Annukka Jauho, Anders Zetterberg, Elina Eriksson, Gert Auer, and Thomas Ried. "Genetic Instability Promotes the Acquisition of Chromosomal Imbalances in T1b and T1c Breast Adenocarcinomas." Analytical Cellular Pathology 22, no. 3 (2001): 123–31. http://dx.doi.org/10.1155/2001/126030.

Full text

Abstract:

In order to evaluate biological and genetic properties of early breast carcinomas we analyzed microdissected tissue from 33 primary breast carcinomas stage T1b and T1c with respect to the nuclear DNA content, the expression pattern of Ki‐67, cyclin A, p27KIP1, p53 and p21WAF1, and chromosomal gains and losses. The results show that T1b carcinomas (6–10 mm,n=17) were frequently near‐diploid (53%) with low proliferative activity and staining patterns of p53 and p21WAF1that suggest the presence of wild type protein. The majority (12/16) of the T1c tumors (11–20 mm), however, was aneuploid, and proliferative activity and p53 expression were increased. Larger tumor size correlated with an increasing number of chromosomal copy number changes and in particular with regional amplifications. High level copy number increases (amplifications), however, were found exclusively in the aneuploid tumors. Amplification events correlated with elevated cyclin A and reduced p27 expression, respectively. Our results suggest that the sequential acquisition of genomic imbalances during tumor progression is accelerated in aneuploid tumors, and may contribute to the increased malignancy potential.

APA, Harvard, Vancouver, ISO, and other styles

32

Heinonen, P. K., J. Isola, and T. Kuoppala. "Immunohistochemical determination of estrogen and progesterone receptors and DNA flow cytometry in endometrial cancer." International Journal of Gynecologic Cancer 4, no. 3 (1994): 169–73. http://dx.doi.org/10.1046/j.1525-1438.1994.04030169.x.

Full text

Abstract:

Estrogen and progesterone receptor contents (ER, PR) were assessed by an immunohistochemical method and DNA ploidy and S-phase by flow cytometry in frozen endometrial cancer tissue sections from 39 cases. Comparison of the immunohistochemical and cytosol assays showed 81% and 84% concordance in ER and PR contents, respectively. An aneuploid DNA pattern was identified in 30% and a high S-phase fraction was found in 33% of 36 specimens studied. Negative ER status was associated with aneuploid and high S-phase fraction. A similar association was found between PR status and high S-phase fraction. Combined analysis of immunohistochemical receptor status and DNA flow cytometry in the same sample makes it possible to identify two strong predictive factors in endometrial adenocarcinoma.

APA, Harvard, Vancouver, ISO, and other styles

33

Quirke, Philip, Michael F. Dixon, Andrew D. Clayden, Paul Durdey, John E. D. Dyson, Norman S. Williams, and Colin C. Bird. "Prognostic significance of DNA aneuploidy and cell proliferation in rectal adenocarcinomas." Journal of Pathology 151, no. 4 (April 1987): 285–91. http://dx.doi.org/10.1002/path.1711510408.

Full text

APA, Harvard, Vancouver, ISO, and other styles

34

Rapallo, Anna, Andrea Sciutto, Elio Geido, Roberto Orecchia, Edmondo Infusini, Natalija Pujic, Emanuele S. G. d’Amore, et al. "K-ras2 Activation and Genome Instability Increase Proliferation and Size of FAP Adenomas." Analytical Cellular Pathology 19, no. 1 (1999): 39–46. http://dx.doi.org/10.1155/1999/257265.

Full text

Abstract:

The possible role of K‐ras2 mutations and aneuploidy toward increase of proliferation and adenoma size in Familial Adenomatous Polyposis (FAP) adenomas is not known. The present study addresses these issues by investigating 147 colorectal adenomas obtained from four FAP patients. The majority of adenomas had size lower than or equal to 10 mm (86%), low grade dysplasia (63%), and were preferentially located in the right colon (60%). Normal mucosa samples were obtained from 19 healthy donors. Three synchronous adenocarcinomas were also investigated. K‐ras2 mutation spectrum was analysed by PCR and Sequence Specific Oligonucleotide (SSO) hybridization, while flow cytometry (FCM) was used for evaluating degree of DNA ploidy and S‐phase fraction. Overall, incidences of K‐ras2 mutations, DNA aneuploidy and high S‐phase values (>7.2%) were 6.6%, 5.4% and 10.5%, respectively. In particular, among the adenomas with size lower than 5 mm, K‐ras2 mutation and DNA aneuploidy frequencies were only slightly above 1%. Statistically significant correlations were found between K‐ras2 and size, DNA ploidy and size and K‐ras2 and S‐phase (p). In particular, among the wild type K‐ras2 adenomas, high S‐phase values were detected in 8% of the cases versus 57% among the K‐ras2 mutated adenomas (p=0.0005). The present series of FAP adenomas indicates that K‐ras2 activation and gross genomic changes play a role toward a proliferative gain and tumour growth in size.

APA, Harvard, Vancouver, ISO, and other styles

35

Bowman, Christopher J., Ruth Zhang, Dana Balitzer, Dongliang Wang, Peter S. Rabinovitch, Bence P. Kővári, Aras N. Mattis, Sanjay Kakar, Gregory Y. Lauwers, and Won-Tak Choi. "Persistent or recurrent Barrett’s neoplasia after an endoscopic therapy session is associated with DNA content abnormality and can be detected by DNA flow cytometric analysis of paraffin-embedded tissue." Modern Pathology 34, no. 10 (June 9, 2021): 1889–900. http://dx.doi.org/10.1038/s41379-021-00832-8.

Full text

Abstract:

AbstractEndoscopic therapy is currently the standard of care for the treatment of high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) in patients with Barrett’s esophagus (BE). Visible lesions are treated with endoscopic mucosal resection (EMR), which is often coupled with radiofrequency ablation (RFA). However, endoscopic therapy may require multiple sessions (one session every 2-3 months) and does not always assure complete eradication of neoplasia. Furthermore, despite complete eradication, recurrences are not uncommon. This study assesses which potential risk factors can predict a poor response after endoscopic sessions. Forty-five BE patients who underwent at least one endoscopic session (EMR alone or ablation with or without preceding EMR) for the treatment of HGD/IMC, low-grade dysplasia (LGD), or indefinite for dysplasia (IND) were analyzed. DNA flow cytometry was performed on 82 formalin-fixed paraffin-embedded samples from the 45 patients, including 78 HGD/IMC, 2 LGD, and 2 IND. Eight non-dysplastic BE samples were used as controls. Three to four 60-micron thick sections were cut from each tissue block, and the area of HGD/IMC, LGD, or IND was manually dissected. Potential associations between clinicopathologic risk factors and persistent/recurrent HGD/IMC following each endoscopic session were examined using univariate and multivariate Cox models with frailty terms. Sixty (73%) of the 82 specimens showed abnormal DNA content (aneuploidy or elevated 4N fraction). These were all specimens with HGD/IMC (representing 77% of that group). Of these 60 HGD/IMC samples with abnormal DNA content, 42 (70%) were associated with subsequent development of persistent/recurrent HGD/IMC (n = 41) or esophageal adenocarcinoma (EAC; n = 1) within a mean follow-up time of 16 months (range: 1 month to 9.4 years). In contrast, only 6 (27%, all HGD/IMC) of the 22 remaining samples (all with normal DNA content) were associated with persistent/recurrent HGD/IMC. For outcome analysis per patient, 11 (24%) of the 45 patients developed persistent/recurrent HGD/IMC or EAC, despite multiple endoscopic sessions (mean: 3.6, range: 1–11). In a univariate Cox model, the presence of abnormal DNA content (hazard ratio [HR] = 3.8, p = 0.007), long BE segment ≥ 3 cm (HR = 3.4, p = 0.002), endoscopic nodularity (HR = 2.5, p = 0.042), and treatment with EMR alone (HR = 2.9, p = 0.006) were significantly associated with an increased risk for persistent/recurrent HGD/IMC or EAC. However, only abnormal DNA content (HR = 6.0, p = 0.003) and treatment with EMR alone (HR = 2.7, p = 0.047) remained as significant risk factors in a multivariate analysis. Age ≥ 60 years, gender, ethnicity, body mass index (BMI) ≥ 30 kg/m2, presence of hiatal hernia, and positive EMR lateral margin for neoplasia were not significant risk factors for persistent/recurrent HGD/IMC or EAC (p > 0.05). Three-month, 6-month, 1-year, 3-year, and 6-year adjusted probabilities of persistent/recurrent HGD/IMC or EAC in the setting of abnormal DNA content were 31%, 56%, 67%, 79%, and 83%, respectively. The corresponding probabilities in the setting of normal DNA content were 10%, 21%, 28%, 38%, and 43%, respectively. In conclusion, in BE patients with baseline HGD/IMC, both DNA content abnormality and treatment with EMR alone were significantly associated with persistent/recurrent HGD/IMC or EAC following each endoscopic session. DNA content abnormality as detected by DNA flow cytometry identifies HGD/IMC patients at highest risk for persistent/recurrent HGD/IMC or EAC, and it also serves as a diagnostic marker of HGD/IMC with an estimated sensitivity of 77%. The diagnosis of HGD/IMC in the setting of abnormal DNA content may warrant alternative treatment strategies as well as long-term follow-up with shorter surveillance intervals.

APA, Harvard, Vancouver, ISO, and other styles

36

Steinbeck, R., C. Steinbeck, E. Postel, H. Busse, B. Havsteen, and G. Auer. "High-resolution 2-dimensional protein mapping of ?diploid? and ?aneuploid? mammary adenocarcinomas." Histochemistry 84, no. 4-6 (1986): 338–41. http://dx.doi.org/10.1007/bf00482960.

Full text

APA, Harvard, Vancouver, ISO, and other styles

37

Mukherjee, M., G. Ge, N. Zhang, D. G. Edwards, P. Sumazin, S. K. Sharan, P. H. Rao, D. Medina, and D. Pati. "MMTV-Espl1 transgenic mice develop aneuploid, estrogen receptor alpha (ERα)-positive mammary adenocarcinomas." Oncogene 33, no. 48 (November 25, 2013): 5511–22. http://dx.doi.org/10.1038/onc.2013.493.

Full text

APA, Harvard, Vancouver, ISO, and other styles

38

Postier, Russell G., Megan R. Lerner, Stan A. Lightfoot, Rick Vannarath, Mary M. Lane, Jay S. Hanas, and Daniel J. Brackett. "DNA Ploidy and Markovian Analysis of Neoplastic Progression in Experimental Pancreatic Cancer." Journal of Histochemistry & Cytochemistry 51, no. 3 (March 2003): 303–9. http://dx.doi.org/10.1177/002215540305100305.

Full text

Abstract:

Computer-assisted analysis of DNA ploidy and nuclear morphology were used to elucidate changes in the cell nucleus that occur during the development of experimental pancreatic cancer. Ductal pancreatic adenocarcinoma was induced in 49 Syrian hamsters by SC injection of N-nitrosobis (2-oxopropyl) amine; twenty hamsters served as controls. Groups of animals were sacrificed every 4 weeks for 20 weeks and adjacent sections of pancreatic tissue were H&E and Feulgen-stained for light microscopy and computer assisted cytometry. Pancreatic ductal cells were classified as normal, atypical, or malignant; tissue inflammation (pancreatitis) was also noted when present. DNA ploidy and nuclear morphology evaluation (Markovian analysis) identified an atypical cell stage clearly distinguishable from either normal or malignant cells; pancreatitis preceded this atypia. The DNA ploidy histogram of these atypical cells revealed a major diploid peak and a minor aneuploid peak. The receiver operator characteristic curve areas for a logistic regression model of normal vs atypical cells was 0.94 and for atypical vs malignant was 0.98, numbers indicative of near-perfect discrimination among these three cell types. The ability to identify an atypical cell population should be useful in establishing the role of these cells in the progression of human pancreatic adenocarcinoma.

APA, Harvard, Vancouver, ISO, and other styles

39

D'Alessandro, Elvira, Maria Luisa Lo Re, Roberto Crisci, Claudio Ligas, and Giorgio Furio Coloni. "Cytogenetic Findings in Primary Non-Small Cell Lung Cancer." Tumori Journal 80, no. 2 (April 1994): 151–56. http://dx.doi.org/10.1177/030089169408000214.

Full text

Abstract:

Non-small cell lung cancer (NSCLC) shows a complex cytogenetic heterogeneity and up to now no particular chromosomal aberration seems to characterize its malignant evolution. We therefore performed cytogenetic analyses of 20 primary NSCLC, 8 adenocarcinomas and 12 squamous cell carcinomas on direct preparations or short-term cultures. Only 1 case was analyzed after long-term culture. Results were obtained from 11 samples and clonal rearrangements were found in 3 cases, a diploid and a near-triploid clone with several aberrations such as i (9q), rob (14; 15) and rob (21; 21) in 1 case, a near-triploid clone in 1 case, and Y chromosome loss in 1 case. Other aberrations found were sporadic, but + 7 aneuploidy and translocations involving 1p were detected in 2 and 3 samples respectively. Although to date it has been very difficult to recognize primary changes in NSCLC, nevertheless a literature review and our results indicate that i(9q) and robertsonian translocations are relevant findings.

APA, Harvard, Vancouver, ISO, and other styles

40

Stolz, Ailine, Norman Ertych, and Holger Bastians. "Loss of the tumour-suppressor genes CHK2 and BRCA1 results in chromosomal instability." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1704–8. http://dx.doi.org/10.1042/bst0381704.

Full text

Abstract:

CHK2 (checkpoint kinase 2) and BRCA1 (breast cancer early-onset 1) are tumour-suppressor genes that have been implicated previously in the DNA damage response. Recently, we have identified CHK2 and BRCA1 as genes required for the maintenance of chromosomal stability and have shown that a Chk2-mediated phosphorylation of Brca1 is required for the proper and timely assembly of mitotic spindles. Loss of CHK2, BRCA1 or inhibition of its Chk2-mediated phosphorylation inevitably results in the transient formation of abnormal spindles that facilitate the establishment of faulty microtubule–kinetochore attachments associated with the generation of lagging chromosomes. Importantly, both CHK2 and BRCA1 are lost at very high frequency in aneuploid lung adenocarcinomas that are typically induced in knockout mice exhibiting chromosomal instability. Thus these results suggest novel roles for Chk2 and Brca1 in mitosis that might contribute to their tumour-suppressor functions.

APA, Harvard, Vancouver, ISO, and other styles

41

Mairinger, Thomas, and Andreas Gschwendtner. "Ploidy determination in prostatic adenocarcinoma using thin histological sections: A more sensitive way of detecting aneuploid tumor clones." Prostate 37, no. 1 (September 15, 1998): 30–35. http://dx.doi.org/10.1002/(sici)1097-0045(19980915)37:1<30::aid-pros5>3.0.co;2-c.

Full text

APA, Harvard, Vancouver, ISO, and other styles

42

Blegen, Harald, John S. Will, B. Michael Ghadimi, Hesed‐Padilla Nash, Anders Zetterberg, Gert Auer, and Thomas Ried. "DNA Amplifications and Aneuploidy, High Proliferative Activity and Impaired Cell Cycle Control Characterize Breast Carcinomas with Poor Prognosis." Analytical Cellular Pathology 25, no. 3 (2003): 103–14. http://dx.doi.org/10.1155/2003/491362.

Full text

Abstract:

In order to explore whether specific cytogenetic abnormalities can be used to stratify tumors with a distinctly different clinical course, we performed comparative genomic hybridization (CGH) of tumors from patients who were diagnosed with metastatic disease after an interval of less than 2 years or who remained free from distant metastases for more than 10 years. All patients presented with distant metastases after mastectomy indicating that none of the patients in this study was cured and free of remaining tumor cells. Tumors in the group of short‐term survivors showed a higher average number of chromosomal copy alterations compared to the long‐term survivors. Of note, the number of sub‐chromosomal high‐level copy number increases (amplifications) was significantly increased in the group of short‐term survivors. In both short‐ and long‐term survivors recurrent chromosomal gains were mapped to chromosomes 1q, 4q, 8q, and 5p. Copy number changes that were more frequent in the group of short‐term survivors included gains of chromosome 3q, 9p, 11p and 11q and loss of 17p. Our results indicate that low‐ and high grade malignant breast adenocarcinomas are characterized by a specific pattern of chromosomal copy number changes. Furthermore, immunohistochemical evaluation of the expression levels of Ki‐67, p27KIP1, p21WAF1, p53, cyclin A and cyclin E revealed a correlation between increased proliferative activity and poor outcome.

APA, Harvard, Vancouver, ISO, and other styles

43

ElSahwi, Karim S., and Alessandro D. Santin. "erbB2Overexpression in Uterine Serous Cancer: A Molecular Target for Trastuzumab Therapy." Obstetrics and Gynecology International 2011 (2011): 1–5. http://dx.doi.org/10.1155/2011/128295.

Full text

Abstract:

Endometrial cancer is the most common female genital tract malignancy in the United States. Type I endometrial cancer is usually diagnosed at an early stage, and has a good prognosis. Type II is very aggressive, and is responsible for most uterine cancer relapses and deaths. Uterine serous adenocarcinomas (USC) constitute the majority of Type II variants. They have a higher propensity for lymph node and distant metastases. They are frequently aneuploid and associated with p53 mutations. erbB2 overexpression in USC has been described. The incidence, which is higher in African Americans, ranges from 18–80%. erbB2 overexpression was found to be associated with higher stage, chemoresistance, and worse survival. Trastuzumab a humanized mAb was approved by the FDA for treatment of breast cancers that overexpress erbB2 in combination with standard chemotherapy. Evidence of trastuzumab activity in USC has been reported in vitro, as well as in case reports of advanced and recurrent cases. Promising results were obtained in these heavily pretreated patients either with trastuzumab alone or in combination with chemotherapy. This supports the hypothesis that trastuzumab may very well be an attractive and viable treatment option for advanced stage USC tumors that overexpress the erbB2, and is worthy of further study.

APA, Harvard, Vancouver, ISO, and other styles

44

Korczak, B., I. B. Robson, C. Lamarche, A. Bernstein, and R. S. Kerbel. "Genetic tagging of tumor cells with retrovirus vectors: clonal analysis of tumor growth and metastasis in vivo." Molecular and Cellular Biology 8, no. 8 (August 1988): 3143–49. http://dx.doi.org/10.1128/mcb.8.8.3143.

Full text

Abstract:

Retrovirus vector infection was used to introduce large numbers of unique genetic markers into tumor cell populations for the purpose of analyzing comparative changes in the clonal composition of metastatic versus that of nonmetastatic tumors during their progressive growth in vivo. The cell lines used were SP1, a nonmetastatic, aneuploid mouse mammary adenocarcinoma, and SP1HU9L, a metastatic variant of SP1. Cells were infected with delta e delta pMoTN, a replication-defective retrovirus vector which possesses the dominant selectable neo gene and crippled long terminal repeats. G418r colonies were obtained at a frequency of 4 x 10(-3). Southern blot analysis of a number of clones provided evidence of random and heritable integration of one or two copies of the proviral DNA. Clonal evolution of primary tumor growth and the nature of lineage relationships among spontaneous metastases and primary tumors were analyzed by subcutaneously injecting 10(5) cells from a pooled mixture of 3.6 x 10(2) G418r SP1HU9L or 10(4) G418r SP1 colonies into syngeneic CBA/J mice. The most striking finding was the relative clonal homogeneity of advanced primary tumors; they invariably consisted of a small number (less than 10) of distinct clones despite the fact that hundreds or thousands of uniquely marked clones had been injected. In the case of the metastatic SP1HU9L cells, the nature of these "dominant" clones varied from one tumor to another. Analysis of a number of lung metastases revealed that a proportion of them were derived from dominant primary tumor clones and were composed of one, and sometimes two, distinct progenitors. In some animals, all the lung metastases were derived from a common progenitor clone, whereas in others, each metastatic nodule had a different progenitor. The results show the following. (i) Retrovirus vector infection can be used to introduce large numbers of unique and stable clonal markers into tumor cell populations. (ii) The progeny of a very limited number of clones dominate in advanced primary tumors. (iii) Mammary carcinoma metastases are of mono- or biclonal origin. The significance of the results is discussed.

APA, Harvard, Vancouver, ISO, and other styles

45

Korczak, B., I. B. Robson, C. Lamarche, A. Bernstein, and R. S. Kerbel. "Genetic tagging of tumor cells with retrovirus vectors: clonal analysis of tumor growth and metastasis in vivo." Molecular and Cellular Biology 8, no. 8 (August 1988): 3143–49. http://dx.doi.org/10.1128/mcb.8.8.3143-3149.1988.

Full text

Abstract:

Retrovirus vector infection was used to introduce large numbers of unique genetic markers into tumor cell populations for the purpose of analyzing comparative changes in the clonal composition of metastatic versus that of nonmetastatic tumors during their progressive growth in vivo. The cell lines used were SP1, a nonmetastatic, aneuploid mouse mammary adenocarcinoma, and SP1HU9L, a metastatic variant of SP1. Cells were infected with delta e delta pMoTN, a replication-defective retrovirus vector which possesses the dominant selectable neo gene and crippled long terminal repeats. G418r colonies were obtained at a frequency of 4 x 10(-3). Southern blot analysis of a number of clones provided evidence of random and heritable integration of one or two copies of the proviral DNA. Clonal evolution of primary tumor growth and the nature of lineage relationships among spontaneous metastases and primary tumors were analyzed by subcutaneously injecting 10(5) cells from a pooled mixture of 3.6 x 10(2) G418r SP1HU9L or 10(4) G418r SP1 colonies into syngeneic CBA/J mice. The most striking finding was the relative clonal homogeneity of advanced primary tumors; they invariably consisted of a small number (less than 10) of distinct clones despite the fact that hundreds or thousands of uniquely marked clones had been injected. In the case of the metastatic SP1HU9L cells, the nature of these "dominant" clones varied from one tumor to another. Analysis of a number of lung metastases revealed that a proportion of them were derived from dominant primary tumor clones and were composed of one, and sometimes two, distinct progenitors. In some animals, all the lung metastases were derived from a common progenitor clone, whereas in others, each metastatic nodule had a different progenitor. The results show the following. (i) Retrovirus vector infection can be used to introduce large numbers of unique and stable clonal markers into tumor cell populations. (ii) The progeny of a very limited number of clones dominate in advanced primary tumors. (iii) Mammary carcinoma metastases are of mono- or biclonal origin. The significance of the results is discussed.

APA, Harvard, Vancouver, ISO, and other styles

46

Negi, Sandeep, Donald Small, and Patrick Brown. "Level of FLT3 Expression in Leukemia Cells Correlates with Specific Histone Modifications and the Presence or Absence of MLL Fusion Genes, Implicating Epigenetic Regulation of FLT3 Expression." Blood 112, no. 11 (November 16, 2008): 4469. http://dx.doi.org/10.1182/blood.v112.11.4469.4469.

Full text

Abstract:

Abstract FLT3 expression level in leukemia cells is associated with specific histone modifications that are associated with presence or absence of MLL fusion genes FLT3 is a class III receptor tyrosine kinase that is normally expressed in hematopoietic stem/progenitor cells. FLT3 expression is lost as hematopoietic cells differentiate. Based on murine knockout studies, FLT3 signaling is known to be important in the development of myeloid progenitors, B lymphoid progenitors, NK cells and dendritic cells. The FLT3 gene is mutated in about one third of acute myeloid leukemia. Apart from the activating mutations, it is also over-expressed in wide range of pre-B and myeloid leukemias. It is particularly highly expressed in leukemias harboring rearrangements of MLL at 11q23. The quantitative level of FLT3 expression in these leukemias is orders of magnitude higher than in germline (wild type) MLL leukemias of similar lineage. The MLL protein is known to have histone methyltransferase activity which resides in the C-terminal SET domain, which predominantly mediates H3K4 methylation. The MLL fusion proteins that result from MLL rearrangements lack the SET domain, but form complexes that interact with DOT1L, a H3K79 methyltransferase. These histone modifying properties of germline and rearranged MLL are central to the function of these proteins as master regulators of target gene expression. The mechanism(s) regulating the level of expression of FLT3 in hematopoietic cells have not been described. Given the association of high FLT3 expression levels with MLL rearrangements, and the recent elucidation of the role of the MLL gene and its fusion proteins in histone modification, we hypothesized that histone modifications may play an important role in the regulation of FLT3 expression. On histone H3, acetylation on lysines 9 and 14 and methylation on lysines 4, 36, and 79 are linked to active transcription, whereas tri-methylation on lysines 9 and 27 is linked to transcriptional repression. We analyzed the modification of histone H3 at lysine 9 (acetylation and tri-methylation) and 14 (acetylation) at the FLT3 promoter in different cell lines including pre-B ALL, monocytic AML, T-cell ALL and adenocarcinoma, with a range of quantitative FLT3 expression. For each of these cell lines, we performed ChIP using H3K9/14 acetyl and H3K9 tri-methyl antibodies followed by Real Time PCR with FLT3 promoter specific primers. The results are summarized in Table 1. Table 1 Cell line Lineage/origin Cytogenetics FLT3 expression mutational status ddC1 FLT3 promoter Acetyl/Methyl Ratio Acetyl H3K9 Methyl H3K9 MV4-11 monocylic AML MLL-AF4 High/TTD 11.1 5.55 2.00 Kopn 8 pre-BALL MLL-ENL High/wt 10.4 5.75 1.81 SEM pre-BALL MLL-AF4 High/wt 13.5 7.9 1.71 Nalm 6 pre-BALL ;(5;12) Low/wt 9 10.1 0.89 Jurkat TALL hypotetraploid Negative/wt 5.4 84 0.64 HeLa cervical CA aneuploid Negative/wt 4.05 9.5 0.43 We found that cell lines with robust FLT3 expression have higher acetylation at H3K9/14 than those with no or low FLT3 expression. Conversely, cell lines with no/low FLT3 expression have higher tri-methylation at H3K9 than those with high FLT3 expression. For individual cell lines, the ratio of acetyl H3K9/14 to tri-methyl H3K9 correlated with FLT3 expression. Furthermore, comparison of similar lineage cell lines with and without MLL rearrangements supports the hypothesis that the MLL mutational status (rearranged vs. germline) may dictate these differences. Kopn 8 (MLL rearranged, high FLT3) and Nalm6 (MLL germline, low FLT3) are both pre-B ALL leukemia cell lines that show converse H3K9/14 acetylation to H3K9 tri-methylation ratios. Together, these findings suggest that FLT3 expression may be controlled in part by histone modifications at its promoter, and that the mutational status of the MLL gene at 11q23 may be an important determinant of these modifications. In ongoing studies that will be reported at the meeting, we are expanding these studies to include additional H3 lysines (such as H3K4 and H3K79), additional cell lines, and primary patient leukemia samples. We are also performing ChIP assays on various sorted fractions of normal human bone marrow to ascertain whether histone modifications play a role in FLT3 expression during normal hematopoiesis.

APA, Harvard, Vancouver, ISO, and other styles

47

Auer, G., K. Heselmeyer, A. Zetterberg, R. Steinbeck, and E. Munck-Wikland. "The relationship between aneuploidy and p53 overexpression during genesis of colorectal adenocarcinoma." Virchows Archiv 424, no. 4 (May 1994). http://dx.doi.org/10.1007/bf00190554.

Full text

APA, Harvard, Vancouver, ISO, and other styles

48

Biesterfeld, Stefan, and Hartwig Schreiber. "The relationship between aneuploidy and p53 overexpression during genesis of colorectal adenocarcinoma." Virchows Archiv 427, no. 4 (December 1995). http://dx.doi.org/10.1007/bf00199398.

Full text

APA, Harvard, Vancouver, ISO, and other styles

49

Bajpai, Manisha, Anshuman Panda, Kristen Birudaraju, James Van Gurp, Amitabh Chak, Kiron M. Das, Parisa Javidian, and Hana Aviv. "Recurring Translocations in Barrett’s Esophageal Adenocarcinoma." Frontiers in Genetics 12 (June 9, 2021). http://dx.doi.org/10.3389/fgene.2021.674741.

Full text

Abstract:

Barrett’s esophagus (BE) is a premalignant metaplasia in patients with chronic gastroesophageal reflux disease (GERD). BE can progress to esophageal adenocarcinoma (EA) with less than 15% 5-year survival. Chromosomal aneuploidy, deletions, and duplication are early events in BE progression to EA, but reliable diagnostic assays to detect chromosomal markers in premalignant stages of EA arising from BE are lacking. Previously, we investigated chromosomal changes in an in vitro model of acid and bile exposure-induced Barrett’s epithelial carcinogenesis (BEC). In addition to detecting changes already known to occur in BE and EA, we also reported a novel recurring chromosomal translocation t(10:16) in the BE cells at an earlier time point before they undergo malignant transformation. In this study, we refine the chromosomal event with the help of fluorescence microscopy techniques as a three-way translocation between chromosomes 2, 10, and 16, t(2:10;16) (p22;q22;q22). We also designed an exclusive fluorescent in situ hybridization for esophageal adenocarcinoma (FISH-EA) assay that detects these chromosomal breakpoints and fusions. We validate the feasibility of the FISH-EA assay to objectively detect these chromosome events in primary tissues by confirming the presence of one of the fusions in paraffin-embedded formalin-fixed human EA tumors. Clinical validation in a larger cohort of BE progressors and non-progressors will confirm the specificity and sensitivity of the FISH-EA assay in identifying malignant potential in the early stages of EA.

APA, Harvard, Vancouver, ISO, and other styles

50

Wido, Thomas M., Jonathan L. Myles, Latha Pisharodi, Tom Sawyer, Kitai Kim, Amira F. Gohara, and John M. Howard. "Aneuploid DNA content in pancreatic adenocarcinoma." International Journal of Pancreatology 7, no. 1-3 (August 1990). http://dx.doi.org/10.1007/bf02924229.

Full text

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'Adenocarcinoma Aneuploidy'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles