Germline susceptibility variants impact clinical outcome and therapeutic strategies for stage III colorectal cancer

Although somatic mutations are the main cause of cancer, underlying germline alterations may affect cancer outcome. There is little information on comprehensive analysis of germline genome sequencing for cancer healthcare strategy. Here we studied the implication of germline cancer-associated variants on cancer counselling and therapeutic strategies by germline whole genome and tumor targeted sequencing. Fifty-five gynecological and 104 colorectal cancer (CRC) patients were enrolled. We identified 22 germline pathogenic variants in 16 cancer-associated genes. Most of them are involved in DNA repair signaling, including MLH1, BRCA1/2, MUTYH, ATM, PMS2, MSH6, BAP1, and FANCA. About 6% of cancer patients presented the secondary findings of germline variants with non-oncogenic impact, mainly on the cardiovascular system which should be carefully monitored during chemotherapy. CRC patients carrying germline susceptibility variants had better disease-free survival than those without variants. Importantly, in the CRC model, the underlying germline alterations mold the tumor somatic alteration landscape. NOTCH1 mutation was the most common somatic mutation in recurrent CRC, implying a potential therapeutic target in adjuvant setting. In conclusion, both tumor genome and germline sequence data have to be analyzed to have a more complete picture of the overall genetic foundation of cancer.