Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer

Abstract

Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.

The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer

“…IP with antibodies against FOXN3 followed by IB with antibodies against representative components of the SIN3A complex showed that the physical interaction between FOXN3 and the SIN3A complex was also detected in T-47D, but not in MDA-MB-231 cells ( Figure 1E, left). The lack of detectable interaction between FOXN3 and the SIN3A complex in MDA-MB-231 cells cies of a variety of tissue origins, including prostate cancer (25), ovarian cancer (26), liver cancer (27), skin cancer (28), laryngeal squamous cell cancer (29), non-small cell lung cancer (30), and glioma (31). Surprisingly, little is known about its role in breast cancer carcinogenesis, especially considering that NEAT1 is estrogen-inducible in prostate cancer cells (25).…”

Genetic basis of hepatitis virus-associated hepatocellular carcinoma: linkage between infection, inflammation, and tumorigenesis

“…Whole genome/exome analysis demonstrated that TP53 and CTNNB1 are the most frequently mutated coding genes, and chromatin modulators, including ARID1A and ARID2, are also recurrently mutated in HCC [24,25,73]. In addition, somatic mutations are detectable in a variety of genes with various oncogenic pathways, including telomere maintenance, Wnt signaling, p53/cell cycle, oxidative stress, epigenetic regulator, PI3 K-AKT-mTOR, MAPK, JAK/STAT, and hepatic differentiation [25].…”

“…Whole genome sequencing analyses revealed more than 9000 point mutations per human HCC sample [73], and somatic mutations are detected in approximately 40-80 protein-coding genes in HCC [19,28,75]. Mutations in the telomerase reverse transcriptase (TERT) promoter are the most prevalent in hepatitis virus-related HCC.…”

Genomic Heterogeneity: Next-Generation Sequencing Enables Biomarker Identification for Hepatocellular Carcinoma

“…Recently, Fujimoto et al reported a WGS analysis on 300 primary liver cancers, 268 of which were HCCs, 8 mixed HCCs and intrahepatic cholangiocarcinomas and 24 intrahepatic cholangiocarcinomas [7]. Three novel cancer driver genes were identified (ASH1L, NCOR1 and MACROD2) with significant validity, due to this study being the largest WGS report currently available on HCC.…”

“…Indeed, definite evidence on genetic and genomic heterogeneity raises the need for biomarker-based personalized medicine [6][7][8]. The ability of NGS to identify molecular subgroups of patients enables the genomic classification of tumors irrespective of cancer type [9].…”