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EPCAM germ line deletions as causes of Lynch syndrome in Spanish patients.

ABSTRACT: The standard genetic test for Lynch syndrome (LS) frequently reveals an absence of pathogenic mutations in DNA mismatch repair genes known to be associated with LS. It was recently shown that germ line deletions in the last exons of EPCAM are involved in the etiology of LS. The aim of this study was to evaluate the prevalence of EPCAM deletions in a Spanish population and the clinical implications of deletion. Probands from 501 families suspected of having LS were enrolled in the study. Twenty-five cases with MSH2 loss were identified: 10 had mutations of MSH2, five had mutations of MSH6, and 10 did not show MSH2/MSH6 mutations. These 25 cases were analyzed for EPCAM deletions using multiplex ligation-dependent probe amplification, and deletions were mapped using long-range PCR analysis. One subject with no MSH2/MSH6 mutations had a large deletion in the EPCAM locus that extended for 8.7 kb and included exons 8 and 9. The tumor exhibited MSH2 promoter hypermethylation. EPCAM deletion analysis followed by MSH2 methylation testing of the tumor is a fast low-cost procedure that can be used to identify mutations that cause LS. We propose that this procedure be incorporated into clinical genetic analysis strategies and present a decision-support flow diagram for the diagnosis of LS.

SUBMITTER: Guarinos C

PROVIDER: S-EPMC2963912 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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EPCAM germ line deletions as causes of Lynch syndrome in Spanish patients.

Guarinos Carla C Castillejo Adela A Barberá Víctor-Manuel VM Pérez-Carbonell Lucía L Sánchez-Heras Ana-Beatriz AB Segura Angel A Guillén-Ponce Carmen C Martínez-Cantó Ana A Castillejo María-Isabel MI Egoavil Cecilia-Magdalena CM Jover Rodrigo R Payá Artemio A Alenda Cristina C Soto José-Luís JL

The Journal of molecular diagnostics : JMD 20100923 6

The standard genetic test for Lynch syndrome (LS) frequently reveals an absence of pathogenic mutations in DNA mismatch repair genes known to be associated with LS. It was recently shown that germ line deletions in the last exons of EPCAM are involved in the etiology of LS. The aim of this study was to evaluate the prevalence of EPCAM deletions in a Spanish population and the clinical implications of deletion. Probands from 501 families suspected of having LS were enrolled in the study. Twenty-f ...[more]

PMID: 20864635

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Project description:BackgroundA large proportion of patients with Lynch syndrome (LS) have MSH2 abnormalities, but genotype-phenotype studies of MSH2 mutations in LS are still lacking. The aim of this study was to comprehensively analyze the clinicopathological characteristics and molecular basis of colorectal cancer (CRC) in patients with uncommon MSH2 cytoplasmic expression.MethodsWe retrospectively reviewed 4195 consecutive cases of CRC patients diagnosed between January 2015 and December 2017 at the Cancer Hospital Chinese Academy of Medical Sciences. Of the 4195 patients with CRC, 69 were indicated to have abnormal MSH2 expression through tumor immunohistochemical staining. Genetic tests, such as next-generation sequencing, large genomic rearrangement (LGR) analysis, microsatellite instability status analysis and genomic breakpoint analysis, were performed. Clinicopathological and molecular characteristics and clinical immunotherapy response were analyzed.ResultsForty-five of 69 patients were identified to have LS with pathogenic germline mutations in MSH2 and/or EPCAM. Of these LS patients, 26.7% were confirmed to harbor large genomic rearrangements (LGRs). Of note, three tumors from two unrelated family pedigrees exhibited a rare cytoplasmic MSH2 staining pattern that was found in LS patients with EPCAM/MSH2 deletions. RNA analysis showed that two novel mRNA fusions of EPCAM and MSH2 resulted in the predicted protein fusion with MSH2 cytoplasmic localization. Analyses of genomic breakpoints indicated that two novel deletions of EPCAM and MSH2 originated from Alu repeat-mediated recombination events. Our study also provides clinical evidence for the beneficial effect of the PD-1 inhibitor pembrolizumab for CRC patients that exhibit cytoplasmic MSH2 staining.ConclusionOur study demonstrates that the rare cytoplasmic MSH2 staining pattern should be fully recognized by pathologists and geneticists. Given the specific genotype-phenotype correlation in LS screening, we advocate that all CRC patients with cytoplasmic MSH2 staining in histology should be screened for LGRs of EPCAM and MSH2.

Project description:BackgroundLynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions.MethodsWe obtained clinical data for 194 carriers of a 3' end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM-MSH2 deletion.Findings93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65-85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM-MSH2 deletion (69% [95% CI 47-91], p=0·8609) or mutations in MSH2 (77% [64-90], p=0·5892) or MLH1 (79% [68-90], p=0·5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p<0·0001). By contrast, women with EPCAM deletions had a 12% [0-27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM-MSH2 deletion (55% [20-90], p<0·0001) or of a mutation in MSH2 (51% [33-69], p=0·0006) or MSH6 (34% [20-48], p=0·0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0·1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer.InterpretationEPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers.

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EPCAM germ line deletions as causes of Lynch syndrome in Spanish patients.

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EPCAM germ line deletions as causes of Lynch syndrome in Spanish patients.

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