Alterations in DNA Damage Repair Genes in Primary Liver Cancer

Alterations in DNA damage repair (DDR) genes produce therapeutic biomarkers. However, the characteristics and significance of DDR alterations remain undefined in primary liver cancer (PLC). Patients diagnosed with PLC were enrolled in the trial (PTHBC, NCT02715089). Tumors and matched blood samples from participants were collected for a targeted next-generation sequencing assay containing exons of 450 cancer-related genes, including 31 DDR genes. The OncoKB knowledge database was used to identify and classify actionable alterations, and therapeutic regimens were determined after discussion by a multidisciplinary tumor board. A total of 357 patients with PLC were enrolled, including 214 with hepatocellular carcinoma, 122 with ICC, and 21 with mixed hepatocellular-cholangiocarcinoma. A total of 92 (25.8%) patients had at least one DDR gene mutation, 15 of whom carried germline mutations. The most commonly altered DDR genes were (5%) and (4.8%). The occurrence of DDR mutations was significantly correlated with a higher tumor mutation burden regardless of the PLC pathologic subtype. For DDR-mutated PLC, 26.1% (24/92) of patients possessed at least one actionable alteration, and the actionable frequency in DDR wild-type PLC was 18.9% (50/265). Eight patients with the mutation were treated by olaparib, and patients with germline truncation mutations showed an objective response. The landscape of DDR mutations and their association with genetic and clinicopathologic features demonstrated that patients with PLC with altered DDR genes may be rational candidates for precision oncology treatment.