BRAF Mutation Testing in Lynch Syndrome Diagnostics: Performance and Efficiency According to Patient's Age

Abstract

Background: BRAF V600E mutations are reportedly 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 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 BRAF testing for exclusion of LS was performed. Findings: Among 969 MSI CRCs from LS carriers in the literature and German HNPCC Consortium, 15 (1∙6%, 95% CI: 0∙9-2∙6%) harboured 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 in 0∙6% (2/339), and inclusion of BRAF testing led to increased costs and higher risk of missing LS patients (1∙2%) compared to other age groups. Interpretation: BRAF testing in patients <50 years is cost-inefficient and carries a high risk of missing a hereditary cancer predisposition. We suggest direct referral of MSI CRC patients <50 years to genetic counseling without BRAF testing. Funding Statement: The study was supported by Wilhelm Sander Foundation (2016.056.1), German Research Foundation (Deutsche Forschungsgemeinschaft, DFG; KFO227, KL2354) and German Cancer Aid (Deutsche Krebshilfe). Declaration of Interests: Dr. Steinke-Lange reports personal fees from AstraZeneca, outside the submitted work. Dr. Vangala received speaker’s honoraria from Roche and Falk and travel grants from Cellgene and Gilead, outside the submitted work. Other authors have no conflict of interests to declare. Ethics Approval Statement: All patients provided informed and written consent. The study was approved by the institutional Ethics Committee.