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

Meta-analyses

Fourteen of the 18 studies in the systematic review were included in the meta-analysis. Two studies[24,34] were excluded, as they had insufficient statistical information to compute an effect size, as were two kin–cohort studies[35,36] because the outcome was the frequency of a family history of colorectal cancer. All studies included in the meta-analysis had moderate quality (NOS = 4–6) based on the Newcastle-Ottawa Scale quality assessment (Table 1). The overall meta-analysis (Figure 3) of 18 assessments of colorectal cancer risk in BRCA1 or BRCA2 mutation carriers found a statistically significant increase in the odds of colorectal cancer for BRCA carriers using a random-effects model (OR = 1.24, 95% CI = 1.02 to 1.51, P = .03).

Figure 3.

Forest plot of the association between overall BRCA mutation carriers and colorectal cancer risk expressed as unadjusted odds ratio. Squares indicate study-specific risk estimates; horizontal lines indicate 95% confidence intervals (CI); diamond indicates summary estimate with the corresponding 95% CI. DerSimonian and Laird random-effects model was used and all statistical tests were two-sided. Test for heterogeneity: χ2 = 19.24, df = 18 (P = .38); I 2 = 8.5%. CRC = colorectal cancer.

Four subgroup meta-analyses that focused on only BRCA1 were performed. The first subgroup meta-analysis included the 10 studies that focused on BRCA1 (Figure 4A) and found that BRCA1 mutation carriers were at higher risk of colorectal cancer (OR = 1.49, 95% CI = 1.19 to 1.85, P < .001). The second subgroup meta-analysis by BRCA1only included the seven cohort studies that reported age- and sex-adjusted estimates (Figure 5A), and yielded a statistically significant risk of colorectal cancer (OR = 1.56, 95% CI = 1.23 to 1.98, P < .001). The third subgroup meta-analysis included four studies that screened for colon cancer and focused on BRCA1 (Supplementary Figure 1A, available online). There was a statistically significant difference in risk of colorectal cancer for BRCA1 carriers (OR = 1.85, 95% CI = 1.39 to 2.47, P < .001). The fourth subgroup meta-analysis included four studies that ascertained the BRCA mutation and focused on BRCA1 (Supplementary Figure 2A, available online). There was no statistically significant difference in the risk of colorectal cancer for BRCA1 carriers (OR = 1.20, 95% CI = 0.85 to 1.71, P = .31).

Figure 4.

Forest plots of the association between BRCA mutation carriers and colorectal cancer risk expressed as unadjusted odds ratio: A) BRCA1; B) BRCA2. Squares indicate study-specific estimates; horizontal lines indicate 95% confidence intervals (CI); diamond indicates summary estimate with the corresponding 95% CI. DerSimonian and Laird random-effects model was used and all statistical tests were two-sided. Test for heterogeneity: A) χ2 = 8.02, df = 9 (P = .53); I 2 = 0.0%. B) χ2 = 1.33, df = 6 (P = .97); I 2 = 0.0%. CRC = colorectal cancer.

Figure 5.

Forest plots of the association between BRCA mutation carriers and colorectal cancer from studies reporting estimates adjusted for age and sex: A) BRCA1; B) BRCA2. Squares indicate study-specific risk estimates; horizontal lines indicate 95% confidence intervals (CI); diamond indicates summary estimate with the corresponding 95% CI. DerSimonian and Laird random-effects model was used and all statistical tests were two-sided. Test for heterogeneity: A) χ2 = 5.76, df = 7 (P = .58); I 2 = 0.0%. B) χ2 = 1.30, df = 5 (P = .94); I 2 = 0.0%. CRC = colorectal cancer.

Supplementary Figure 1.

Forest plots of the association between BRCA mutation carriers and colon cancer from studies screened for colon cancer A) BRCA1. B) BRCA2. Squares indicate study specific risk estimates; horizontal lines indicate 95% confidence intervals (CI); diamond indicates summary estimate with the corresponding 95% CI. DerSimonian and Laird random-effects model was used and all statistical tests were two-sided. Test for heterogeneity: A) Chi-squared= Chi-squared=0.64, df=3 (P=0.89); I-squared=0.0%. B) Chi-squared=0.01, df=1 (P=0.93); I-squared=0.0%.

Four subgroup meta-analyses that focused on BRCA2 only were performed. The first subgroup meta-analysis of seven studies focused on BRCA2 (Figure 4B) found no statistically significant risk of colorectal cancer for mutation carriers (OR = 1.10, 95% CI = 0.77 to 1.58, P = .61). The second subgroup meta-analysis by BRCA2 only included the cohort studies that reported age- and sex-adjusted estimates. The analysis of six studies (Figure 5B) revealed no statistically significant risk of colorectal cancer between carriers and noncarriers (OR = 1.09, 95% CI = 0.75 to 1.58, P = .66). The third subgroup meta-analysis of two studies that screened for colon cancer and focused on BRCA2 (Supplementary Figure 1B, available online) found no statistically significant risk of colorectal cancer for BRCA2 carriers (OR = 1.22, 95% CI = 0.70 to 2.12, P = .49). Lastly, a subgroup meta-analysis of three studies that ascertained BRCA mutation and focused on BRCA2 (Supplementary Figure 2B, available online) found no statistically significant risk of colorectal cancer for BRCA2 carriers (OR = 1.02, 95% CI = 0.58 to 1.82, P = .94).

Supplementary Figure 2.

Forest plots of the association between BRCA mutation carriers and colorectal cancer from studies that ascertained mutation A) BRCA1. B) BRCA2. Squares indicate study specific risk estimates; horizontal lines indicate 95% confidence intervals (CI); diamond indicates summary estimate with the corresponding 95% CI. DerSimonian and Laird random-effects model was used and all statistical tests were two-sided. Test for heterogeneity: A) Chi-squared=3.00, df=5 (P=0.70); I-squared=0.0%. B) Chi-squared=0.94, df=3 (P=0.82); I-squared=0.0%.

The contour-enhanced funnel plot of standard error by effect estimate (Figure 6) showed, in general, symmetry. Coupled with the Egger test (P = .17) indicating symmetry in the funnel plot, there was no evidence of publication bias in the studies included in the meta-analysis.

Figure 6.

Contour-enhanced funnel plot of standard error by effect estimate for overall meta-analysis of the association between BRCA mutation and colorectal cancer.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....