Molecular characterization-based multi-omics analyses in primary liver cancer using the Japanese version of the genome atlas.

Abstract

Primary liver cancer (PLC) is classified into hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular and intrahepatic cholangiocarcinoma (CHC). We investigated the genomic landscape of PLC according to the histological classification and established a cross-histological molecular subtyping for PLC by a multi-omics analysis. We analyzed 265 PLC cases with whole-exome sequencing and DNA copy number analyses and 251 cases with gene expression profiling. The cohort included HCC (n=223, 84%), ICC (n=34, 13%), and CHC (n=8, 3%). Mutation analyses identified histological type-specific driver genes, such as CTNNB1 in HCC and KRAS, IDH1, and PIK3CA in ICC, and ARID1A and KMT2C in CHC. The tumor suppressor gene TP53 mutation was detected in 21.1% of HCC, 16.1% of ICC, and 25.0% of CHC cases. Other well-characterized tumor suppressor genes included RB1, which was mutated in 2.8% of HCC and 3.2% of ICC; and PTEN, which was mutated in 1.4% of HCC, 3.2% of ICC, and 12.5% of CHC cases. DNA copy number analyses identified focal amplifications, with NUF2 (1q23.3) the most frequently detected as an amplified gene in all 3 types (HCC, 3.8%; CHC, 12.5%, ICC, 3.2%). Molecular subtyping for PLC based on the multi-omics analysis identified three subtypes, one of which was associated with recurrence after resection and amplified genes located at chromosome 8q. Our dataset serves as a fundamental resource for genomic medicine for PLC in Japan and identified amplified genes located at chromosome 8q as promising therapeutic targets for the subgroup with a poor prognosis.