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

Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here a team led by researchers at the RIKEN Center for Integrative Medical Sciences provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. This comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. The research team 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.

Genome-wide search for mutational clusters in noncoding regions

lncRNA

(a) Genome-wide analysis of significantly mutated regions. Negative log-transformed P values corresponding to the significance of the mutation rate in each 500-bp region are plotted across the chromosomes. The Bonferroni-corrected genome-wide significance threshold is P = 2.3 × 10−8 (dashed black line). Representative significantly mutated regions are indicated by arrows. Crosses represent mutational clusters including coding exons, and filled circles represent those in noncoding (nc) regions. CTCF bs, CTCF binding site. (bd) Functional data for three significantly mutated regions, including the WDR74 promoter (b), the MED16 enhancer (c), and the chromosome 18 noncoding region (d). For each region, the positions of indels (blue) and point mutations (red) are shown using the UCSC Genome Browser (top panels). Orange arrows indicate the commonly mutated regions. In b and c, black and red or blue bars show relative luciferase activity compared with that of mock-transfected cells (white bars) for the wild-type region and the observed mutant regions. Values represent means ± s.d.; n = 3 technical replicates. Mutant regions showing significantly higher activity than the wild-type region in the two HCC cell lines are indicated by gray asterisks, and those with lower activity are indicated by black asterisks.

Fujimoto A et al. (2016) Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet [Epub ahead of print]. [abstract]

Leave a Reply

Your email address will not be published. Required fields are marked *

*