Somatic BRAF-V600E Mutations in Familial Colorectal Cancer

Abstract

The BRAF gene is mutated in 4% to 12% of unselected colorectal cancers, particularly those with high microsatellite instability and in premalignant lesions, such as serrated adenomas and hyperplastic polyps. However, it has been shown that activating BRAF mutations are almost never found in tumors from hereditary nonpolyposis colorectal cancer patients. To evaluate the role of oncogenic BRAF mutations in non-hereditary nonpolyposis colorectal cancer/ non-familial adenomatous polyposis familial colorectal cancer, we did a mutation screening of the most common BRAF mutation, the V600E mutation, in 194 colorectal tumors from patients with a positive family history of the disease. The BRAF-V600E mutation was identified in 100% (8 of 8) of microsatellite-unstable tumors and in 9.7% (18 of 186) of microsatellite-stable tumors. Interestingly, families with extracolonic tumors showed a much higher mutation frequency (17.5%) compared with families with colonic cancer only (3.5%; P = 0.009). In addition, we studied colonoscopic results from 448 family members who had been under colonoscopic surveillance for several years. Subjects from families where the V600E mutation was identified had less adenomas compared with those from families where no BRAF mutation had been found (odds ratio, 8.5; 95% confidence interval, 1.1-64.6). These findings indicate that adenomas might be less important in the cancer development in the group of families with BRAF-V600E mutations and indirectly support a previous hypothesis that tumors might develop through the hyperplastic polyp-serrated adenoma pathway. In conclusion, our results suggest that BRAF-V600E mutations are mainly involved in colorectal cancer families characterized by an increased risk of other common malignancies. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2270 -3)

Increased Cancer Predisposition in Family Members of Colorectal Cancer Patients Harboring the p.V600E BRAF Mutation: a Population-Based Study

“…A correlation between a family history of CRC and patients with MSI-H BRAF Mut tumors has been previously reported (20). However, that study (20) used a selected cohort of familial colorectal patients, and only eight MSI-H tumors were evaluated.…”

“…A correlation between a family history of CRC and patients with MSI-H BRAF Mut tumors has been previously reported (20). However, that study (20) used a selected cohort of familial colorectal patients, and only eight MSI-H tumors were evaluated. Samowitz et al (9) used a large number of unselected population-based CRC patients and reported a significant association between patients with MSS BRAF Mut tumors and a family history of CRC (OR = 4.23; 95% CI, 1.65-10.84).…”

“…A small number of studies (9,19,20) have investigated the association between CRC patients with BRAF Mut tumors and a family history of cancer, only one of which used a population-based approach (9). A correlation between a family history of CRC and patients with MSI-H BRAF Mut tumors has been previously reported (20).…”

“…In addition, there is evidence to suggest that CRC patients with the somatic BRAF mutation have a stronger family history of cancer compared with patients with BRAF wild-type tumors (9,19,20). However, the evidence is limited, and patients who have MSI-H BRAF mutation tumors are generally regarded as sporadic cases (11).…”

Ethnicity and Risk for Colorectal Cancers Showing Somatic BRAF V600E Mutation or CpG Island Methylator Phenotype

“…In addition, familial syndromes associated with BRAF mutation-bearing tumors have been described from Australia and Sweden (29,38). There is also indirect evidence regarding an association between ethnicity and the risk of colorectal cancer with CIMP and BRAF mutation from a study of hyperplastic polyposis syndrome, which is a rare condition characterized by multiple serrated polyps and tumors with CIMP and BRAF mutation.…”