Comprehensive genomic analysis of early and late-onset hepatocellular carcinoma.

Abstract

e16186 Background: Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer and is a leading cause of cancer-related death worldwide. HCC is highly therapy-resistant, and biomarker-driven therapies are emerging as important treatment options. Risk factors have been implied to distinguish early and late-onset patients. A high prevalence of non-cirrhotic HCC attributed to hepatitis B virus infection was found in young Asian patients. In late-onset patients, genetic aberrations accumulated with age in liver cirrhosis and other chronic liver diseases could provide the basis of tumorigenesis. Thus, diverse genomic alteration modes may underlie HCC of different onset ages, but the analysis is lacking. This study aims to explore genomic distinctions underlying early and late-onset HCC, thus facilitating personalized biomarker-driven treatments. Methods: The plasma and tumor samples from 222 Chinese HCCs underwent genomic profiling with hybridization capture-based targeted next-generation sequencing. The patients were categorized into early (male < 40 years or female < 50 years) or late (male ≥ 40 years or female ≥ 50 years) onset in accordance with the American Association for the Study of Liver Diseases guideline. We compared the clinical and molecular characteristics and explored differences between the early and late-onset cohorts. Results: The late-onset cohort accounts for 83.3% (185/222) of all HCC cases, and its male incidence rate is significantly higher than that of early-onset (88.6% vs 56.8%, p< 0.0001). More younger cases have a family history of HCC (21.6% vs 14.6%). The mean somatic alteration numbers per patient are comparable between early and late-onset (8.30 vs 9.92). While TP53, TERT, and MCL1 are the most frequently mutated genes in both cohorts, we identified eight genes with significantly higher mutation frequencies in early-onset. OncoKB Levels 1 to 4 actionable alterations are present in 48.7% and 44.3% of younger and older patients, respectively, whereas the early-onset cohort has a significant enrichment of actionable MDM2 alterations (10.8% vs 1.1%, p= 0.0078). The prevalence of DNA Damage Response and Repair (DDR) gene mutations (35.1% vs 48.6%) and tumor mutation burden (TMB, mean: 4.17 muts/Mb vs 8.11 muts/Mb) are elevated in older patients. Notably, individuals harboring DDR mutations are associated with higher TMB in late-onset (mean TMB in DDR-mutated: 10.44 vs DDR- wildtype: 5.90, p= 0.0016) but not early-onset (mean TMB in DDR-mutated: 3.47 vs DDR- wildtype: 4.54, p= 0.280). Conclusions: Tumors from early and late-onset HCC demonstrated differences in genes and other biomarkers relevant to cancer biology and response to therapy. Specifically, DDR-mutated patients in the late-onset cohort are associated with higher TMB and may benefit from combining targeted and immunotherapy. Future studies are warranted to examine the response to biomarker-driven treatment strategies.