Germline mutations of mismatch repair genes (e.g. MLH1, MSH2, MSH6, PMS2 and MUTYH) are well-known to be associated with Lynch syndrome, characterized by early-onset colorectal cancer in patients younger than 50 years. However, only 4-13.5% of early-onset CRC can be attributed to Lynch syndrome, implying the involvement of additional cancer susceptibility genes. A JAMA CRC report from the Ohio State University indicates that about one out of six early-onset CRC patients has a hereditary cancer susceptibility. The researchers used a 25-genes hereditary cancer panel to test 450 early-onset CRC patients. They found 75 pathogenic germline variants in 72 patients, including 13 patients harboring variants in genes not traditionally considered as CRC risk genes (ATM, CHEK2, BRCA1/2, CDKN2A and PALB2). Importantly, about 33% of patients did not meet the NCCN Guidelines for at least one identified mutation. Therefore, gene testing with multi-gene panels could be considered for all patients with early-onset CRC. This approach would also enable female relatives of patients with BRCA1/2 mutations to evaluate their breast and ovarian cancer risk. Finally, multi-gene panels can help researchers to explore more VUS and reclassify a part of VUS through family studies. In conclusion, multi-gene testing enables a better understanding of the prevalence and spectrum of germline mutations in various cancers susceptibility genes.
1. Pearlman R, et al,. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2016 Dec 15.