Racial difference of mutational signature in hepatocellular carcinoma

Abstract

Aim: Previous studies have demonstrated the racial disparities of new incidence and mortality rate of hepatocellular carcinoma (HCC) patients, but the racial differences in the tumor characteristics causing these disparities remain unclear. Methods: We collected genomic mutation profile of 589 HCC patients, including Asian-Korea (n = 231), Asian-TCGA (n = 156), White-TCGA (n = 176), and Black-TCGA (n = 16). We applied a non-negative factorized matrix algorithm to decipher the mutational signatures of HCC patients, compared racial differences of mutational signature, performed molecular subtyping analysis of HCC patients based on their composition of mutational signatures, and evaluated their influence on clinical outcome. Results: Asian patients showed a significantly higher level of SBS96F-aristolochic acid exposure signature related to the widespread usage of Chinese herbs in East Asia, and they also showed higher SBS96B-MMR at T > C mutations but lower SBS96D-MMR at C > T mutations than White patients, suggesting the heterogeneous mechanisms related to defective DNA mismatch repair across races. Asian-Korea patients showed a significantly higher SBS96C-tobacco chewing and aflatoxin exposure than the other three populations, indicating the higher levels of aflatoxin contamination in food and environment in this area. The SBS96G-Unclear signature was also observed to be significantly higher in Asian-Korea patients, and their dominated subgroup patients showed better prognosis for both disease-free and overall survival probability. Conclusion: Our study found racial differences of mutational signatures to be associated with differences in diverse genetic backgrounds and environmental factors, which might help guide the personalized treatment of HCC patients.