Penetrance of Colorectal Cancer Among Mismatch Repair Gene Mutation Carriers: A Meta-Analysis

Abstract

Background: Lynch syndrome, the most common colorectal cancer (CRC) syndrome, is caused by germline mismatch repair (MMR) genes. Precise estimates of age-specific risks are crucial for sound counseling of individuals managing a genetic predisposition to cancer, but published risk estimates vary. The objective of this work is to provide gene-, sex-, and age-specific risk estimates of CRC for MMR mutation carriers that comprehensively reflect the best available data.

Methods: We conducted a meta-analysis to combine risk information from multiple studies on Lynch syndrome-associated CRC. We used a likelihood-based approach to integrate reported measures of CRC risk and deconvolved aggregated information to estimate gene- and sex-specific risk.

Results: Our comprehensive search identified 10 studies (8 on MLH1, 9 on MSH2, and 3 on MSH6). We estimated the cumulative risk of CRC by age and sex in heterozygous mutation carriers. At age 70 years, for male and female carriers, respectively, risks for MLH1 were 43.9% (95% confidence interval [CI] = 39.6% to 46.6%) and 37.3% (95% CI = 32.2% to 40.2%), for MSH2 were 53.9% (95% CI = 49.0% to 56.3%) and 38.6% (95% CI = 34.1% to 42.0%), and for MSH6 were 12.0% (95% CI = 2.4% to 24.6%) and 12.3% (95% CI = 3.5% to 23.2%).

Conclusions: Our results provide up-to-date and comprehensive age-specific CRC risk estimates for counseling and risk prediction tools. These will have a direct clinical impact by improving prevention and management strategies for both individuals who are MMR mutation carriers and those considering testing.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the literature review for our meta-analysis. EMBASE = Excerpta Medica dataBASE; NLP = natural language processing; CRC = colorectal cancer; MMR = mismatch repair.

Figure 2.

Age-specific colorectal cancer risk for mismatch repair gene mutation carriers. Panels A, B, and C correspond to MLH1, MSH2, and MSH6 mutation carriers, respectively. DerSimonian and Laird random effects model results: the age range is divided into 10-year intervals. Within each we show the meta-analytic estimate from the DerSimonian and Laird random effects model (thick vertical black bars). The height of vertical bars represents 95% confidence intervals. Likelihood-based approach results: Smooth blue and orange lines represent penetrance estimated from the likelihood-based approach by yearly age. Blue corresponds to male carriers, and orange corresponds to female carriers.

Figure 3.

Colorectal cancer risk stratified by studies on unscreened or no prior surgery population (top) or unspecified (ie, likely a mix of screened and unscreened populations) (bottom). Panels A, B, and C correspond to MLH1, MSH2, and MSH6 mutation carriers, respectively. DerSimonian and Laird random effects model results: The age range is divided into 10-year intervals. Within each we show the meta-analytic estimate from the DerSimonian and Laird random effects model (thick vertical black bars). The height of vertical bars represents 95% confidence intervals. Likelihood-based approach results: Smooth blue and orange lines represent penetrance estimated from the likelihood-based approach by yearly age. Blue corresponds to male carriers, and orange corresponds to female carriers.

Figure 4.

Leave-1-study-out sensitivity analysis for mutation carriers. Panels A, B, and C correspond to MLH1, MSH2, and MSH6 mutation carriers, respectively.  Bold solid lines: Cumulative penetrance estimates of CRC based on our likelihood-based approach. Dashed lines: Cumulative penetrance estimates by yearly age of CRC from leave-1-study-out tests of sensitivity. Blue corresponds to male carriers, and orange corresponds to female carriers. Visually, small deviations of a dashed line from the solid line suggest our meta-analysis is robust to the removal of that study.

Figure 5.

Cumulative penetrance estimates of colorectal cancer from current meta-analysis and MMRpro. Panels A, B, and C correspond to MLH1, MSH2, and MSH6 mutation carriers, respectively. Estimates from current meta-analysis and MMRpro are denoted by solid and dotted lines, respectively. Blue corresponds to male carriers, and orange corresponds to female carriers.