Microsatellite Instability, Mismatch Repair Deficiency, and BRAF Mutation in Treatment-Resistant Germ Cell Tumors

2009 ◽  
Vol 27 (13) ◽  
pp. 2129-2136 ◽  
Author(s):  
Friedemann Honecker ◽  
Hendrik Wermann ◽  
Frank Mayer ◽  
Ad J.M. Gillis ◽  
Hans Stoop ◽  
...  
Keyword(s):  
Germ Cell ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Braf Mutation ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors ◽  
Braf V600e ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Mmr Deficiency

Purpose Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are associated with cisplatin resistance in human germ cell tumors (GCTs). BRAF mutation (V600E) is found in MSI colorectal cancers. The role of RAS/RAF pathway mutations in GCT treatment response is unknown. Patients and Methods Two patient cohorts were investigated: 100 control GCTs (50 seminomas and 50 nonseminomas) and 35 cisplatin-based chemotherapy-resistant GCTs. MMR proteins were analyzed by immunohistochemistry, and eight microsatellite loci were examined for MSI. Tumors were assessed for specific BRAF and KRAS mutations. Results Resistant tumors showed a higher incidence of MSI than controls: 26% versus 0% in two or more loci (P < .0001). All resistant tumors were wild-type KRAS, and two controls (2%) contained a KRAS mutation. There was a significantly higher incidence of BRAF V600E mutation in resistant tumors compared with controls: 26% versus 1% (P < .0001). BRAF mutations were highly correlated with MSI (P = .006), and MSI and mutated BRAF were correlated with weak or absent staining for hMLH1 (P = .017 and P = .008). Low or absent staining of hMLH1 was correlated with promoter hypermethylation (P < .001). Tumors lacking expression of hMLH1 or MSH6 were significantly more frequent in resistant GCTs than in controls (P = .001 and 0.0036, respectively). Within the subgroup of resistant tumors, patients with MSI showed a trend to longer progression-free survival (P = .068). Conclusion We report for the first time a correlation between a gene mutation—BRAF V600E—and cisplatin resistance in nonseminomatous GCTs. Furthermore, a correlation between MMR deficiency, MSI, and treatment failure is confirmed.

Defective mismatch repair proteins and microsatellite instability in young Mexican patients with colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14708-e14708
Author(s):  
Arturo Quintanilla Guzman ◽  
Arturo Luevano Gonzalez ◽  
Augusto Rojas Martinez ◽  
Juan Pablo Flores Gutierrez ◽  
Juan Francisco Gonzalez Guerrero ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Young Patients ◽  
Gene Promoter ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Braf Mutations ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms ◽  
Msi Analysis

e14708 Background: Colorectal carcinoma (CRC) is prevalent malignancy and a third of the cases affect young patients. 15% of CRC have microsatellite instability (MSI) due to disruptions in mismatch repair (MMR) genes, like germline mutations (3%) and hypermethylation of the MLH1 gene promoter associated to the BRAF V600E mutation (12%). The aim of this work was to assess MMR abnormalities in tumors of Mexican CRC patients under 50 years old. Methods: CRC paraffin-embedded tissues of 47 patients with available demographic/clinical data were studied by immunohistochemistry (IHC) for MLH1/MSH2, qPCR with specific probes/sequencing for the BRAF V600E mutation, and conventional PCR (5 markers) for MSI analysis. Results: Female:Male ratio was 0.81:1. Most of the cases were classified as TNM Stage II, were located in the cecum, invaded the serous coat, and showed intestinal-type histology. 20 samples showed alterations in MMR protein expression. MLH1, MSH2, and combined deficiency of both proteins were detected in 17, 4, and 4 tumors, respectively. No BRAF mutations were detected. MSI analysis restricted to the 20 altered IHC samples showed MSI in 10 tumors (3 MSI-low and 7 MSI-high tumors). The four cases with MLH1/MSH2 deficiency, showed MSI-high pattern. Conclusions: We found 42.6% cases with defective MMR expression. No epigenetic abnormalities associated to BRAF V600E mutation were registered. The lack of MSI in ten tumors with deficient MMR may be due to alternate DNA repair mechanisms. Acknowledgments. Work supported by the CHIBCHA Project (European Commission7FP grant #223678).

Specific Clinical and Biological Features Characterize Inflammatory Bowel Disease–Associated Colorectal Cancers Showing Microsatellite Instability

2007 ◽  
Vol 25 (27) ◽  
pp. 4231-4238 ◽  
Author(s):  
Magali Svrcek ◽  
Jamila El-Bchiri ◽  
Alexandra Chalastanis ◽  
Emilie Capel ◽  
Sylvie Dumont ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Bowel Disease ◽  
Target Genes ◽  
Low Frequency ◽  
Colorectal Cancers ◽  
Braf Mutations ◽  
Inflammatory Bowel ◽  
Mmr Deficiency

Purpose Microsatellite instability (MSI) due to mismatch repair (MMR) deficiency has been reported to occur at variable frequencies in inflammatory bowel disease–associated intestinal neoplasias (IBD-Ns). We investigated a large series of IBD-N for associations between MSI and several biologic and clinical parameters related to tumors, patients, and their treatment. Patients and Methods A total of 277 IBD-Ns in 205 patients were screened for MSI. Biologic and clinical variables of patients with high levels of DNA microsatellite instability high (MSI-H) were collected and compared with those associated with 33 MSI-H non-IBD colorectal cancers (CRCs). Results A total of 27 IBD-Ns from 17 patients were found to be MSI-H. Compared with sporadic MSI-H CRCs, patients presented with a younger age at diagnosis, and there was no female predominance and no right-sided predominance. Unlike sporadic MSI-H CRCs, MSI-H IBD-Ns presented with heterogeneous mismatch repair defects involving MLH1, MSH2, MSH6, or PMS2, and a low frequency of MLH1 promoter methylation. They exhibited frequent BRAF mutations and frameshift mutations in genes containing coding repeat sequences. Conclusion The mechanisms underlying MMR deficiency in MSI-H IBD-Ns are different from those in sporadic MSI-H tumors and seem to be more related to those observed in hereditary MSI-H tumors. However, BRAF mutations were observed in MSI-H IBD-Ns, similar to sporadic MSI-H tumors, but unlike hereditary MSI-H tumors. Finally, the mutational events in target genes for instability are the same in MSI-H IBD-N tumors as in non-IBD sporadic and hereditary colorectal MSI-H cancers, indicating a colon-related repertoire of target gene alterations.

scholarly journals Hereditary non-polyposis colorectal cancer is predicted to contribute towards colorectal cancer in young South African blacks

2009 ◽  
Vol 105 (1/2) ◽  
Author(s):  
L. Cronjé ◽  
P.J. Becker ◽  
A.C. Paterson ◽  
M. Ramsay
Keyword(s):  
Colorectal Cancer ◽  
South Africa ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Braf V600e ◽  
Cancer Tissue ◽  
Braf Mutations ◽  
Tissue Samples ◽  
Molecular Features ◽  
Black Patients

A disproportionately large number of young (less than 50 years) black patients present with colorectal cancer (CRC) in South Africa. Although a phenomenon previously described elsewhere in Africa, its specific molecular basis, whether sporadic or hereditary, has not been established. Molecular analysis of these tumours could link them to the features known to be associated with specific types of hereditary colorectal cancer, specifically through examination of levels of microsatellite instability, promoter methylation and the presence or absence of KRAS and BRAF mutations. The molecular features of cancer tissue samples from 44 CRC cases of black and white patients in South Africa were accordingly retrospectively analysed without knowledge of family history. Compared with samples from older blacks (>50 years), those from young black patients presented more often with a low methylation phenotype (CIMP-L) and high levels of microsatellite instability (MSI-H). Furthermore, as determined by real-time PCR using probe technology, the tissues from 35% of young blacks showed mutations within exon 1 of the KRAS gene. The BRAF-V600E mutation was only evident in the case of a single young black patient. Based on these results it seems likely that a proportion of CRC cases in young black patients from South Africa develop through the accumulation of mutations resulting in a mismatch repair deficiency linked to MSI-H and, possibly, germline mutations in the mismatch repair genes. The features in these patients are consistent with a diagnosis of the Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome. This finding has important implications for patient management and suggests that family members may be at high risk for CRC.

Molecular Mechanisms of Resistance in Testicular Germ Cell Tumors - clinical Implications

2018 ◽  
Vol 18 (10) ◽  
pp. 967-978 ◽  
Author(s):  
Katarina Kalavska ◽  
Vincenza Conteduca ◽  
Ugo De Giorgi ◽  
Michal Mego
Keyword(s):  
Germ Cell ◽  
Molecular Mechanisms ◽  
Cisplatin Resistance ◽  
Apoptotic Cell ◽  
Germ Cell Tumors ◽  
Treatment Resistance ◽  
Experimental Models ◽  
Testicular Germ Cell Tumors ◽  
Testicular Germ Cell ◽  
Repair Capacity

Testicular germ cell tumors (TGCTs) represent the most common malignancy in men aged 15-35. Due to these tumors’ biological and clinical characteristics, they can serve as an appropriate system for studying molecular mechanisms associated with cisplatin-based treatment resistance. This review describes treatment resistance from clinical and molecular viewpoints. Cisplatin resistance is determined by various biological mechanisms, including the modulation of the DNA repair capacity of cancer cells, alterations to apoptotic cell death pathways, deregulation of gene expression pathways, epigenetic alterations and insufficient DNA binding. Moreover, this review describes TGCTs as a model system that enables the study of the cellular features of cancer stem cells in metastatic process and describes experimental models that can be used to study treatment resistance in TGCTs. All of the abovementioned aspects may help to elucidate the molecular mechanisms underlying cisplatin resistance and may help to identify promising new therapeutic targets.

scholarly journals Distinct BRAF (V600E) and KRAS Mutations in High Microsatellite Instability Sporadic Colorectal Cancer in African Americans

2009 ◽  
Vol 15 (4) ◽  
pp. 1155-1161 ◽  
Author(s):  
Krishan Kumar ◽  
Hassan Brim ◽  
Francis Giardiello ◽  
Duane T. Smoot ◽  
Mehdi Nouraie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
African Americans ◽  
Microsatellite Instability ◽  
Braf V600e ◽  
Sporadic Colorectal Cancer ◽  
Kras Mutations

scholarly journals MP81-15 GENETIC BASIS FOR CISPLATIN RESISTANCE IN PATIENTS WITH ADVANCED GERM CELL TUMORS (GCT)

2016 ◽  
Vol 195 (4S) ◽  
Author(s):  
Aditya Bagrodia ◽  
Byron Lee ◽  
William Lee ◽  
Eugene Cha ◽  
John Sfakianos ◽  
...  
Keyword(s):  
Germ Cell ◽  
Genetic Basis ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors

scholarly journals The Frequency of DNA Mismatch Repair Deficiency Is Very Low in Surgically Resected Lung Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Naoki Yanagawa ◽  
Noriyuki Yamada ◽  
Ryo Sugimoto ◽  
Mitsumasa Osakabe ◽  
Noriyuki Uesugi ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Cell Carcinoma ◽  
Mismatch Repair ◽  
Squamous Cell ◽  
Lung Carcinoma ◽  
The Other ◽  
Dna Mismatch ◽  
Mmr Deficiency

IntroductionDNA mismatch repair (MMR) deficiency leads to changes in the length of nucleotide repeat sequences of tumor DNA. In that situation, DNA replicational errors occur and accumulate during DNA replication. As a result, this mechanism frequently affects the coding regions of oncogenes and tumor suppressor genes and causes carcinogenesis. Recently, DNA MMR deficiency has been recognized as a predictive biomarker for immunotherapy. The aim of this study is to examine the frequency of DNA MMR deficiency and clinicopathological characteristics in surgically resected lung carcinoma (LC) and their correlation.MethodsA total of 1153 LCs were examined. Tissue microarrays were constructed. The status of MMR deficiency was evaluated by immunohistochemical analysis of MMR protein expression (hMLH1, hMSH2, hMSH6, and hPMS2). Microsatellite instability analysis, BRAF mutation, and MLH1 methylation analysis were performed for cases that showed MMR deficiency.ResultsOnly 2 of the 1153 cases (0.17%) showed a loss of hMLH1/hPMS2 protein expression. They also had high levels of microsatellite instability (MSI-H), had neither MLH1 promoter methylation nor BRAF mutation, and were male smokers. Histopathologically, one was a squamous cell carcinoma, and the other was combined small cell carcinoma with squamous cell carcinoma. Regarding PD-L1 protein expression, one had high expression, and the other had none.ConclusionThe frequency of MMR deficiency was very low in LC. However, our two cases were non-adenocarcinoma and differed from previous studies. Because of its very low frequency, MMR deficiency is not a practical biomarker to predict the effect of immune checkpoint inhibitors in LC.

Quality Control and Telemedicine for BRAF V600E Mutations in Papillary Thyroid Carcinomas

2015 ◽  
Vol 4 (2) ◽  
pp. 12-30 ◽  
Author(s):  
Niki Margari ◽  
Abraham Pouliakis ◽  
Aris Spathis ◽  
Emmanouil Mastorakis ◽  
Efthymios Karakostas ◽  
...  
Keyword(s):  
Quality Control ◽  
Braf Mutation ◽  
Image Features ◽  
Classification And Regression Tree ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Cell Nuclei ◽  
Braf Mutations ◽  
Mutation Status ◽  
Thyroid Carcinomas

The assessment of BRAF V600E mutations is important for prognosis and treatment of Papillary Thyroid Carcinomas (PTC), the standard methods for their identification are molecular biology techniques. In this study, the potential of image morphometry applied to cell nuclei and sequentially the use of a Classification And Regression Tree (CART) is investigated, in order to: identify morphometric features useful to characterize BRAF mutations, and to eventually produce an algorithm identifying BRAF mutation status. The 140 studied cases had histological confirmation and known BRAF mutation status identified via real-time PCR. The analysis revealed that nuclear features contributing to BRAF mutation status identification via the CART model are related mostly to nuclear color. According to the results there is evidence that BRAF V600E mutations can be identified by measurable image features. Therefore, the proposed method is useful for quality control of BRAF V600E mutations on cytological slides, can serve as alternative to PCR method and may be used for remote assessment.

scholarly journals Epigenetic Remodeling through Downregulation of Polycomb Repressive Complex 2 Mediates Chemotherapy Resistance in Testicular Germ Cell Tumors

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 796 ◽  
Author(s):  
Ratnakar Singh ◽  
Zeeshan Fazal ◽  
Andrea K. Corbet ◽  
Emmanuel Bikorimana ◽  
Jennifer C. Rodriguez ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors ◽  
Parental Origin ◽  
Testicular Germ Cell Tumors ◽  
Polycomb Repressive Complex ◽  
Testicular Germ Cell ◽  
Polycomb Repressive Complex 2 ◽  
H3k27 Methylation ◽  
Resistant Cells

A greater understanding of the hypersensitivity and curability of testicular germ cell tumors (TGCTs) has the potential to inform strategies to sensitize other solid tumors to conventional chemotherapies. The mechanisms of cisplatin hypersensitivity and resistance in embryonal carcinoma (EC), the stem cells of TGCTs, remain largely undefined. To study the mechanisms of cisplatin resistance we generated a large panel of independently derived, acquired resistant clones from three distinct parental EC models employing a protocol designed to match standard of care regimens of TGCT patients. Transcriptomics revealed highly significant expression changes shared between resistant cells regardless of their parental origin. This was dominated by a highly significant enrichment of genes normally repressed by H3K27 methylation and the polycomb repressive complex 2 (PRC2) which correlated with a substantial decrease in global H3K27me3, H2AK119 ubiquitination, and expression of BMI1. Importantly, repression of H3K27 methylation with the EZH2 inhibitor GSK-126 conferred cisplatin resistance to parental cells while induction of H3K27 methylation with the histone lysine demethylase inhibitor GSK-J4 resulted in increased cisplatin sensitivity to resistant cells. A gene signature based on H3K27me gene enrichment was associated with an increased rate of recurrent/progressive disease in testicular cancer patients. Our data indicates that repression of H3K27 methylation is a mechanism of cisplatin acquired resistance in TGCTs and that restoration of PRC2 complex function is a viable approach to overcome treatment failure.

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