Early-onset small bowel and colorectal cancer patients with BRCA mutations: Actionable variants in atypical presentations.

Abstract

545 Background: The paradigm of genetic panel testing for hereditary colorectal cancer (CRC) continues to emerge. An association between Hereditary Breast and Ovarian Cancer (HBOC) syndrome and early onset CRC and has been reported, though only significantly associated with BRCA1 mutations. Guidelines do not include CRC in the HBOC spectrum. We describe nine early-onset ( < 55 years) gastrointestinal (GI) cancer patients with germline mutations in BRCA1 or BRCA2 to highlight actionable findings that would have been missed by traditional CRC genetic testing. Methods: The nine affected patients underwent genetic testing using NGS-based multi-gene cancer panels. Genomic DNA variants were identified and classified according to ACMG criteria. Patient medical histories were obtained by referring clinician and documented on test requisition forms, and were de-identified for analysis. Results: Nine patients had a pathogenic (P) variant in BRCA1 (three cases) or BRCA2 (six cases). Four patients were under the age of 32 at the time of their CRC diagnosis. Of the nine cases, only one met NCCN testing criteria for HBOC syndrome. All patients were negative for P variants in the canonical CRC genes (APC, MUTYH, MLH1, MSH2, MSH6, PMS2, EPCAM). Conclusions: In this series, nine unrelated patients with early-onset CRC were found to carry a BRCA1 or BRCA2 mutation. The presence of BRCA mutations in these CRC patients is alone not strong evidence of causation; however, it suggests that clinicians should consider expanded panel testing in the presence of complex family histories, as these patients would have been found negative by traditional genetic tests. As the phenotypic spectrum of classical cancer syndromes is expanded by broad panel-based testing, it is important to identify patients that fall outside traditional diagnostic criteria, as some patients will have actionable findings in unexpected genes.