TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease‐related hepatocellular carcinoma

The number of patients with nonalcoholic fatty liver disease (NAFLD)‐related hepatocellular carcinoma (HCC) is increasing. To understand the molecular features of the tumor phenotype, we aimed to clarify the overall landscape of genetic aberrations accumulated in NAFLD‐related HCC. Of 247 HCC patients who underwent hepatectomy during 2010 to 2014 at a single center in Japan, 10 were diagnosed with NAFLD‐HCC based on strict clinical and pathologic criteria. We analyzed the genetic aberrations of 11 NAFLD‐HCC tumor samples from these 10 patients by whole‐exome sequencing, targeted sequencing of the selected genes, and copy number variation studies. Whole‐exome sequencing revealed a mean somatic mutation rate of 1.86 per megabase, and 12 genes were recurrently mutated in NAFLD‐HCCs. Targeted sequencing of the 26 selected genes (12 recurrently mutated genes in whole‐exome sequencing and 14 representative HCC‐associated genes) revealed that TERT promoter mutations occurred in 9 of 11 HCCs (82%), followed by CTNNB1 (45%) and TP53 (36%) mutations. Array‐based copy number variation studies identified recurrent gains at 1q and 8q, and recurrent losses at 1p, 4q, 6q, 8p, 13q, 16p, 17p, and 18q. Notably, chromosome 8p loss occurred in all of the NAFLD‐HCC samples. The current study provided the characteristics of genetic aberrations in NAFLD‐HCC and suggested that TERT promoter mutations and chromosome 8p loss mainly contribute to NAFLD‐related liver carcinogenesis.