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Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer
- Source :
- Clinical Gastroenterology and Hepatology. 3:254-263
- Publication Year :
- 2005
- Publisher :
- Elsevier BV, 2005.
-
Abstract
- Background & Aims: Recently, an alternative pathway of tumorigenesis has been identified in the colorectum associated with serrated precursor lesions, variable levels of microsatellite instability (MSI-V), and driven in part by activating mutations in the BRAF proto-oncogene (V599E). Somatic BRAF mutations in hereditary nonpolyposis colon cancer (HNPCC) are rarely observed. Here, we discuss their role in the development of other familial colorectal cancers (CRC). We studied non-FAP, non-HNPCC CRC families characterized by tumors that varied in their level of MSI between individual members. Methods: A subset of tumors from a total of 55 collected (25 polyp and 30 cancers) from 43 individuals across 11 families underwent pathology review, examination for V599E using allele-specific polymerase chain reaction, and for methylation of the MINT31 CpG island. Results: All MSI-V families met the current revised Bethesda Guidelines and 6 of 11 (55%) met the Amsterdam I criteria. V599E was observed in 12 of 19 (63%) polyps and 14 of 20 (70%) cancers (4 of 4 high MSI, 2 of 4 low MSI, and 8 of 12 stable MSI), a significant increase over HNPCC (0 of 15 or 0%), and unselected CRC (30 of 197 or 15.2%) (P < .05). Eight of the 10 (80%) cancers that underwent analysis showed hypermethylation of MINT31. CRCs showed early age at onset and were more likely to show a serrated architecture than unselected CRCs (P < .05). Conclusion: These data provide evidence that the families described here represent a syndrome of familial CRC that is distinct from HNPCC. High levels of BRAF mutation and MINT31 hypermethylation suggest an origin in the serrated pathway of CRC development.
- Subjects :
- Male
Proto-Oncogene Proteins B-raf
Oncology
congenital, hereditary, and neonatal diseases and abnormalities
medicine.medical_specialty
Pathology
Adenomatous polyposis coli
Colorectal cancer
medicine.disease_cause
Proto-Oncogene Mas
Genomic Instability
Familial adenomatous polyposis
Internal medicine
Humans
Medicine
Genetic Predisposition to Disease
neoplasms
Hepatology
biology
CpG Island Methylator Phenotype
business.industry
Gastroenterology
Microsatellite instability
DNA Methylation
medicine.disease
digestive system diseases
Hyperplastic Polyp
CpG site
Mutation
biology.protein
CpG Islands
Female
Colorectal Neoplasms
business
Carcinogenesis
Microsatellite Repeats
Subjects
Details
- ISSN :
- 15423565
- Volume :
- 3
- Database :
- OpenAIRE
- Journal :
- Clinical Gastroenterology and Hepatology
- Accession number :
- edsair.doi.dedup.....c78a80395e82a772d2edc8099bcaf98b