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

AbstractBackground and aimsBRAFV600E 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 somaticBRAFmutation testing in MLH1-deficient MSI CRC patients to exclude LS. As sporadicBRAF-mutant MSI CRC is a disease of the elderly, while LS-associated CRC usually occurs at younger age, we hypothesized that the efficacy ofBRAFtesting in LS diagnostics may be age-dependent.MethodsWe systematically compared the prevalence ofBRAFV600E 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 theBRAFtesting for exclusion of LS was performed.ResultsAmong 969 MSI CRCs from LS mutation carriers from the literature and German HNPCC Consortium, 15 (1.6%, 95% CI: 0.9-2.6%) harboredBRAFmutations. 6/7 LS patients withBRAF-mutant CRC and reported age were <50 years. Among unselected MSI CRCs, 44.8% (339/756) harboredBRAFmutations, 92.3% (313/339) of which were detected in patients >60 years. In MSI CRC patients <50,BRAFmutations were detected only in 0.6% (2/339), and the inclusion ofBRAFtesting led to increased costs and higher risk of missing LS patients (1.2%) compared to other age groups.ConclusionBRAFtesting 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 priorBRAFtesting.