Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer

Colorectal cancers resulting from defective DNA mismatch repair can occur in both hereditary non-polyposis colon cancer (HNPCC) and in the sporadic setting. They are characterised by a high level of microsatellite instability (MSI-H) and superficially resemble each other in that they are frequently...

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Bibliographic Details
Published in:Familial cancer 2004, Vol.3 (2), p.101-107
Main Authors: McGivern, A, Wynter, C V A, Whitehall, V L J, Kambara, T, Spring, K J, Walsh, M D, Barker, M A, Arnold, S, Simms, L A, Leggett, B A, Young, J, Jass, J R
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Colonic Neoplasms - diagnosis
Colonic Neoplasms - genetics
Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis
Colorectal Neoplasms, Hereditary Nonpolyposis - genetics
Diagnosis, Differential
DNA Methylation
DNA Mutational Analysis
Female
Humans
Male
Microsatellite Repeats
Middle Aged
Polymerase Chain Reaction
Promoter Regions, Genetic - genetics
Proto-Oncogene Proteins B-raf - genetics
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Summary:Colorectal cancers resulting from defective DNA mismatch repair can occur in both hereditary non-polyposis colon cancer (HNPCC) and in the sporadic setting. They are characterised by a high level of microsatellite instability (MSI-H) and superficially resemble each other in that they are frequently located in the proximal colon and share features such as circumscribed tumour margins and tumour-infiltrating lymphocytes. However, significant differences can be demonstrated at the molecular level including widespread promoter hypermethylation and BRAF -activating mutations which occur significantly less often in HNPCC. In this study, we sought to determine whether the presence of widespread promoter hypermethylation and BRAF mutations would exclude HNPCC. We investigated the methylation status of four methylated in tumour markers (MINTs 1,2,12 and 31), and the promoter regions of 5 genes hMLH1, HPP1, MGMT, p16INK4A and p14ARF, in 21 sporadic MSI-H colorectal cancers and compared these with 18 cancers from HNPCC patients. The methylation status of CpG islands were determined by either methylation specific PCR (MSP) or combined bisulfite restricton analysis (COBRA). In addition we considered the BRAF mutation status of 18 HNPCC tumours and 19 sporadic MSI-H cancers which had been previously determined by RFLP analysis and confirmatory sequencing. Methylation of the promoter regions in target genes occurred less frequently within the HNPCC tumours (27% of analyses), compared with the sporadic MSI-H tumours (59% of analyses) (P < 0.001). Methylation of MINTs 1, 2, 12 and 31 occurred in 4% of analyses for HNPCC tumours contrasted with 73% for sporadic MSI-H tumours (P < 0.001). BRAF mutations were detected in 74% of sporadic tumours but none of the HNPCC cancers tested. The total number of genes and MINTs methylated in HNPCC was lower than in MSI-H colorectal tumours. No HNPCC tumour showed evidence of widespread promoter hypermethylation or BRAF mutation suggesting this feature could be used as a discriminator between familial and sporadic cases.
ISSN:1389-9600
1573-7292
DOI:10.1023/b:fame.0000039861.30651.c8