BRAFmutation testing of MSI CRCs in Lynch syndrome diagnostics: performance and efficiency according to patient’s age

Background and aims BRAF V600E mutations have been reported to be associated with sporadic microsatellite-unstable (MSI) colorectal cancer (CRC), while rarely detected in CRCs of Lynch syndrome (LS) patients. Therefore, current international diagnostic guidelines recommend somatic BRAF mutation testing in MLH1-deficient MSI CRC patients to exclude LS. As sporadic BRAF -mutant MSI CRC is a disease of the elderly, while LS-associated CRC usually occurs at younger age, we hypothesized that the efficacy of BRAF testing in LS diagnostics may be age-dependent. Methods We systematically compared the prevalence of BRAF V600E mutations in LS-associated CRCs and MSI CRCs from population-based cohorts in different age groups as available from published studies, databases, and population-based patient cohorts. Cost calculations and sensitivity analysis of the BRAF testing for exclusion of LS was performed. Results Among 969 MSI CRCs from LS mutation carriers from the literature and German HNPCC Consortium, 15 (1.6%, 95% CI: 0.9-2.6%) harbored BRAF mutations. 6/7 LS patients with BRAF -mutant CRC and reported age were 60 years. In MSI CRC patients <50, BRAF mutations were detected only in 0.6% (2/339), and the inclusion of BRAF testing led to increased costs and higher risk of missing LS patients (1.2%) compared to other age groups. Conclusion BRAF testing in patients <50 years is cost-inefficient and carries the highest risk of missing LS patients among different age groups. We suggest direct referral of MSI CRC patients <50 years to genetic counseling without prior BRAF testing.