Family History of Colorectal Cancer in BRAF p.V600E-Mutated Colorectal Cancer Cases

Abstract

Background Previous reports suggest that relatives of CRC-affected probands carrying the BRAF p.V600E mutation are at an increased risk of colorectal (CRC) and extracolonic cancers (ECCs). In this study, we estimated the association between a family history (FH) of either CRC or ECC and risk of CRC with a BRAF p.V600E mutation. Methods Population-based CRC cases (probands; aged 18–59years at diagnosis), recruited irrespective of family cancer history, were characterised for BRAF p.V600E mutation and mismatch repair (MMR) status. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Results The 690 eligible probands demonstrated a mean age at CRC diagnosis of 46.9±7.8years, with 313 (47.9%) reporting a FH of CRC and 53 (7.7%) that were BRAF-mutated. Probands with BRAF-mutated, MMR-proficient CRCs were less likely to have a FH of CRC than probands that were BRAF-wildtype (OR=0.46, 95%CI=0.24–0.91; p=0.03). For probands with a BRAF-mutated CRC, the mean age at diagnosis was older for those with a CRC-affected first- or second-degree relative (49.3±6.4 years) compared with those without a FH (43.8±10.2 years; p=0.04). The older the age at diagnosis of CRC with the BRAF p.V600E mutation, the more likely these probands demonstrated a FH of CRC (OR=1.09 per year of age; 95%CI=1.00–1.18; p=0.04). Conclusions Probands with early-onset, BRAF-mutated and MMR-proficient CRC were less likely to have a FH of CRC than probands that were BRAF-wildtype. Impact These findings provide useful insights for cancer risk assessment in families and suggest that familial or inherited factors are more important in early onset, BRAF-wildtype CRC.

Role of tumour molecular and pathology features to estimate colorectal cancer risk for first-degree relatives

“…A subset of this data has been previously reported highlighting an inverse association between BRAF-mutated CRC and family history of CRC. 27 In contrast, three other studies support an association between a family history of CRC and an increased risk of the BRAF-mutated CRC. [55][56][57] One potential explanation for the discrepancy in findings between this study and the previous reports might be the difference in the mean age at diagnosis of the CRC cases.…”

<b><i>RAS, BRAF,</i></b> and <b><i>TP53</i></b> Gene Mutations in Taiwanese Colorectal Cancer Patients

“…Our results are similar to those of Kwon et al [28] who found that the prevalence of BRAF mutations in 92 CRC patients was 3.3% using the PNA-mediated PCR clamping method. BRAF mutations have been associated with inferior survival for CRC [37,38,39] and a reduced likelihood of a family history of CRC in a young age group [40]. Zlobec et al [41] showed the coexistence of high-level CpG island methylator phenotype (CIMP) with BRAF mutation.…”

Does risk of endometrial cancer for women without a germline mutation in a DNA mismatch repair gene depend on family history of endometrial cancer or colorectal cancer?

“…A fluorescent allele-specific PCR assay was used to detect the somatic T>A mutation at nucleotide 1799 in exon 15 of the BRAF gene ( BRAF V600E) as has been previously described [22, 23]. Methylation of the MLH1 gene promoter was measured in all MSI-high and MSI-low cases with sufficient tumor DNA and a random sample of microsatellite stable cases.…”