BRCA1 and BRCA2 Gene Mutations and Colorectal Cancer Risk

Systematic Review and Meta-analysis

Mok Oh; Ali McBride; Seongseok Yun; Sandipan Bhattacharjee; Marion Slack; Jennifer R. Martin; Joanne Jeter; Ivo Abraham

Disclosures

J Natl Cancer Inst. 2018;110(11):1178-1189. 

In This Article

Abstract and Introduction

Abstract

Background: Investigations of the associations with colorectal cancer have yielded conflicting results. The aim of our study was to synthesize the research on colorectal cancer risks in BRCA mutation carriers by means of a systematic review and quantitatively by means of meta-analyses overall and in subgroups of BRCA mutation carriers.

Methods: We searched PubMed/MEDLINE, Embase, Cochrane, Scopus, and ProQuest Dissertation & Theses. Unadjusted odds ratios (ORs) were used to derive pooled estimates of colorectal cancer risk overall and in subgroups defined by mutation type (BRCA1 or BRCA2), cancer type (colorectal or colon cancer), study design (age–sex-adjusted or crude), and ascertainment method (ascertained or inferred genotyping). The associations were evaluated using random-effect models. All statistical tests were two-sided.

Results: Eighteen studies were included in the systematic review: five cohort studies with ascertained BRCA mutation, six cohort studies involving pedigree analysis, five case–control studies, and two kin–cohort studies. Of these, 14 were used in the meta-analysis, which revealed a statistically significant increased risk of colorectal cancer in overall BRCA mutation carriers (OR = 1.24, 95% confidence interval (CI) = 1.02 to 1.51, P = .03). In subgroup meta-analyses by BRCA type, BRCA1 mutation was associated with increased risk of colorectal cancer (OR = 1.49, 95% CI = 1.19 to 1.85, P < .001), but BRCA2 was not (OR = 1.10, 95% CI = 0.77 to 1.58, P = .61). In subgroup meta-analyses of studies reporting estimates adjusted for age and sex, an increased risk of colorectal cancer for BRCA1 (OR = 1.56, 95% CI = 1.23 to 1.98, P < .001), but not for BRCA2 (OR = 1.09, 95% CI = 0.75 to 1.58, P = .66) was observed. Analyses stratified by ascertainment method found no association between BRCA mutation and colorectal cancer risk.

Conclusion: The meta-analysis results provide clinicians and health-care regulatory agencies with evidence of the increased risk of colorectal cancer in BRCA1 mutation carriers, but not in BRCA2.

Introduction

Mutations of DNA tumor suppressor genes have been associated with many cancer types.[1] These genes encode diverse proteins that help control cell proliferation and thus block tumor development.[2] The BRCA1 and BRCA2 tumor suppressor genes are involved in homologous recombination, known to be an error-free repair pathway for DNA double-strand breaks.[3,4] The association between germline mutations in the BRCA1 and BRCA2 genes and diverse types of cancer has been studied since the genes were discovered in the mid-1990s.[5,6] Individuals with BRCA1 or BRCA2mutations show statistically significant increased lifetime risks of up to 84% for breast cancer and 40% for ovarian cancer.[7–10] These mutations have also been found to be associated with prostate, pancreatic, stomach, and colorectal cancer,[11,12] but the magnitude of this risk is not clear.

Allelic losses at the BRCA1 locus have been detected in almost 50% of sporadic colorectal cancers.[13] One of the early retrospective cohort studies in North America and Western Europe examined data from families with ovarian or breast cancer and found the relative risk of colorectal cancer in BRCA1 mutation carriers to be 4.11 (95% confidence interval [CI] = 2.36 to 7.15).[14] Other studies reported the risk of developing colorectal cancer in relatives of familial breast cancer patients to be higher than in the general population.[15,16] However, studies on the incidence of colorectal cancer in BRCA mutation carriers have shown contradictory results, and generalizable estimates of the magnitude of the risk of colorectal cancer in BRCA mutation carriers remain lacking. A qualitative appraisal and narrative review by Sopik et al.[17] concluded that an increased risk of colorectal cancer exists in high-risk families and that the risk is limited to BRCA1 mutation carriers younger than age 50 years. Hence, the purpose of our study was to synthesize the research on colorectal cancer risks in BRCA mutation carriers, qualitatively by means of a systematic review and quantitatively by means of overall and stratified meta-analyses.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....