NGS analysis of germline mutation profile of patients with hepatocellular carcinoma in China.

Abstract

10585 Background: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide with very poor prognosis. Many studies have focused on oncogene characteristics, however, the germline landscape of Chinese HCC patients has not been fully clarified. The purpose of this study is to assess the inherited genetic factors regarding germline mutations in Chinese HCC patients. Methods: Genetic mutations were reviewed in 1670 Chinese HCC patients who underwent hybridization capture based next-generation sequencing (NGS). The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Of 1670 patients with HCC, 110 (6.7%) patients were identified to carry 111 pathogenic variants(P) or likely pathogenic variants(LP) in 112-cancer predisposition gene panel, and there was no age difference between P/LP group and non-P/LP group (average age: 57 vs 56, p = 0.64). The most frequently germline mutated genes were BRCA1/2 (11.7%), followed by ATM(4.5%), BLM(4.5%), ERCC2(4.5%), ERCC3(4.5%) and BRIP1(3.6%), ERCC4(3.6%), FANCD2(3.6%), MUTYH(3.6%), RAD50(3.6%). Of all the 111 germline mutations, 47% (n = 52) lay in the Homologous Recombination Repair (HRR) pathways. Both in P/LP group and non-P/LP group, the most frequently somatic mutated genes were TP53, TERT and MUC16. 7/110(6.4%)of patients in P/LP group were high TMB(≥10 mutations/megabase) and 131/1560(8.5%) in non-P/LP group. There was no statistical difference in TMB between P/LP and non-P/LP group. Conclusions: Taken together, we have presented the spectrum of pathogenic germline mutations in Chinese HCC patients. P/LP germline variants in cancer predisposition genes were detected in 6.7% of those patients, and predisposition genes associated with HCC risk needs further investigation. Inherited genetics should not be overlooked in HCC as there are important implications for precision treatment, future risk of cancers, and familial cancer risk.