Genome-wide DNA methylation profiling during metabolic dysfunction-associated steatohepatitis-related hepatocarcinogenesis in patients in Japan and the United States

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This study aimed to compare ethnicity-related differences in DNA methylation profiles during metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocarcinogenesis in patients from Japan and the United States (US). Genome-wide DNA methylation analysis using the Infinium assay was performed in 36, 148 and 36 samples of normal liver tissue (NLT), non-cancerous liver tissue showing MASH, and MASH-related hepatocellular carcinoma (HCC), respectively (220 samples in total), from the Japan and US cohorts. Principal component analysis revealed that MASH had a distinct DNA methylation profile differing from that of NLT, and that the MASH profiles in the two cohorts differed from each other. DNA methylation alterations of cancer-related genes in MASH were inherited by or strengthened in MASH-related HCC itself, resulting in expression alterations. DNA methylation alterations of FGFR2, FUT4, B3GNT5 and MOSC1 in the precancerous MASH stage were shared by the two cohorts, suggesting that such genes are commonly associated with MASH-related hepatocarcinogenesis. On the other hand, it was suggested that DNA methylation alterations of ZNF611 and SAMD10, and those of SHC1, are involved specifically in MASH-related hepatocarcinogenesis in the Japan and the US cohorts, respectively. These findings suggest that DNA methylation alterations, which may reflect race and lifestyle, are associated with MASH-related hepatocarcinogenesis.

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