Background: Hepatobiliary cancers are genetically and clinically heterogenous. Current precision therapy for hepatobiliary cancers is limited and only benefits a minority. New biomarkers and precision therapy are needed to improve clinical outcome of hepatobiliary cancer patients.
Method: Tumor samples of 379 hepatocellular cancer (HCC) patients and 490 biliary tract cancer (BTC) patients from Chinese population were genetically profiled using the targeted next-generation sequencing. Nonsynonymous mutations and copy number variations (CNV) of tumor samples were analyzed. The R package ReactomePA was used for pathway enrichment analysis. Tumor mutation burden was calculated by counting all nonsynonymous mutations per megabase of coding sequence. Subgroup analyses were performed to test the correlation between clinical, pathological, and genetic covariates.
Results: The pathway analysis of somatic mutations in HCC and BTC showed mutation enrichment in the DNA damage repair (DDR) pathway (including TP53), of which mutations were found over 70% patients (78% in HCC and 73% in BTC). The most prevalent DDR mutations occurred in TP53 (56% in BTC and 65% in HCC) and ATM (8.2% in BTC and 4.5% in HCC), which was followed by ATR in HCC (4.2%) and BRCA2 in BTC (4.1%). A co-occurrence of DDR wild type and low TMB was found. In DDR-mutant and DDR-wild-type groups, the percentage of TMB-high patients was 15% vs. 4% for HCC, and 15% vs. 0% for BTC, which suggests a negative predictive value of DDR wild type for high TMB. In both HCC and BTC, mutations in homologous recombination repair (HRR), mismatch repair (MMR) and base excision repair (BER) pathways were significantly correlated with high TMB (p-value < 0.001). Interestingly, compared to HCC, BTC showed additional associations of the mutations in Fanconi anemia and cell-cycle checkpoint pathways with high TMB (p-value < 0.001). Among the four BTC subtypes, TMB-high patients were relatively enriched in gall bladder cancer and peri-hilar cholangiocarcinoma (13% vs. 9% in intra-hepatic and distal cholangiocarcinoma). Furthermore, gall bladder cancer showed higher than average abundance of BRCA2 mutations (6.3%), which was recently proposed as an actionable target for PARP inhibitor treatment. All CNVs of DDR genes were copy number loss and they were much more frequent in HCC than BTC (18% vs. 6%). However, CNVs of DDR genes were found not significantly associated with high TMB.
Conclusions: Our genetic profiling of hepatobiliary cancer mutations demonstrated that DDR mutations in specific pathways could serve as useful biomarkers for rational patient selection for targeted therapy or immunotherapy.
Citation Format: Zhenhao Fang, Qiuxiang Ou, Rui Liu, Hua Bao, Xue Wu, Yang Shao. Genetic profiling of DNA damage repair genes in hepatobiliary cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2041.