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Molecular and clinical characteristics of MSH6 germline variants detected in colorectal cancer patients.
- Source :
-
Oncology reports [Oncol Rep] 2013 Dec; Vol. 30 (6), pp. 2909-16. Date of Electronic Publication: 2013 Oct 02. - Publication Year :
- 2013
-
Abstract
- The MSH6 gene is one of the mismatch repair genes involved in Lynch syndrome and its mutations account for 10-20% of Lynch syndrome. Although previous studies suggested that the difference of the geographical region affects the clinical phenotype of Lynch syndrome, there has been no report on the detailed features of Japanese Lynch syndrome patients carrying an MSH6 mutation. The aim of the present study was to investigate the clinical and molecular features of MSH6 mutation carriers in Japan. Surgically resected 1720 colorectal carcinoma specimens were screened by microsatellite instability (MSI) testing and the MSI-high cases were subjected to a germline mutation analysis of the mismatch repair genes MLH1, MSH2 and MSH6. We investigated the clinical and molecular features of the MSH6 variants, such as the family cancer history, pathological findings, immunohistochemistry, methylation status of the MLH1 promoter and BRAF mutation in the colorectal tumor. Furthermore, the impact of the missense variants on MSH6 protein was predicted by using in silico tools. We identified nine novel pathogenic mutations and eight unclassified missense variants. Among the eight missense variants, three were suspected pathogenic by in silico analysis. We also found that most colorectal cancers in the MSH6 mutation carrier were diagnosed after the age of 50 and were localized distally. Furthermore, the mean age at diagnosis of endometrial cancer in Japanese MSH6 mutation carriers (49.2 years) was earlier than previous reports from Western countries (56.5 years). These results may improve the surveillance program for Japanese MSH6 mutation carriers.
- Subjects :
- Adaptor Proteins, Signal Transducing genetics
Adult
Aged
Aged, 80 and over
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms pathology
Female
Gene Expression Regulation, Neoplastic
Germ-Line Mutation
Humans
Lymphatic Metastasis genetics
Lymphatic Metastasis pathology
Male
Middle Aged
MutL Protein Homolog 1
MutS Homolog 2 Protein genetics
Neoplasm Staging
Nuclear Proteins genetics
Prognosis
Carcinogenesis genetics
Colorectal Neoplasms genetics
DNA Methylation genetics
DNA-Binding Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1791-2431
- Volume :
- 30
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Oncology reports
- Publication Type :
- Academic Journal
- Accession number :
- 24100870
- Full Text :
- https://doi.org/10.3892/or.2013.2781