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Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.

ABSTRACT: Large genomic rearrangements (LGRs) in DNA-mismatch-repair (MMR) genes, particularly among MSH2 gene, are frequently involved in the etiology of Lynch syndrome (LS). The Multiplex Ligation and Probe Amplification assay (MLPA) is commonly used to identify such alterations. However, in most cases, the MLPA-identified alteration is not characterized at the molecular level, which might be important to identify recurrent alterations and to analyze the molecular mechanisms underlying these mutational events. Probands from a cohort of Lynch Syndrome families were screened for point mutation in MMR genes, subsequently the MLPA assay was used for LGR screening. The identified MLPA alteration was confirmed by cDNA, CGH-microarrays or massive parallel sequencing. In this study, we have delimited the region of 11 LGRs variants on MSH2 locus. Six of them were fully characterized the breakpoints and 9 of them were considered pathogenic. According to our data, LGR on MSH2 locus constituted the 10.8% (9 out of 83) of pathogenic germline alterations found in LS. The frequency of colorectal cancer (CRC) and endometrial cancer (EC) in LGR carriers was 55% and 11% respectively. Analysis of the breakpoint sequences revealed that in 3 cases, deletions appeared to originate from Alu-mediated recombination events. In the remaining cases, sequence alignment failed to detect microhomology around the breakpoints. The present study provides knowledge on the molecular characterization of MSH2 LGRs, which may have important implications in LS diagnosis and Genetic Counseling. In addition, our data suggests that nonhomologous events would be more frequently involved in the etiology of MSH2 LGRs than expected.

SUBMITTER: Romero A

PROVIDER: S-EPMC3770653 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.

Romero Atocha A Garre Pilar P Valentin Olivia O Sanz Julian J Pérez-Segura Pedro P Llovet Patricia P Díaz-Rubio Eduardo E de la Hoya Miguel M Caldés Trinidad T

PloS one 20130911 9

Large genomic rearrangements (LGRs) in DNA-mismatch-repair (MMR) genes, particularly among MSH2 gene, are frequently involved in the etiology of Lynch syndrome (LS). The Multiplex Ligation and Probe Amplification assay (MLPA) is commonly used to identify such alterations. However, in most cases, the MLPA-identified alteration is not characterized at the molecular level, which might be important to identify recurrent alterations and to analyze the molecular mechanisms underlying these mutational ...[more]

PMID: 24039744

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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.

Dataset Information

Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.

Publications

Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.

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