Integrative analysis of somatic mutations altering microRNA targeting in cancer genomes

PLoS One. 2012;7(10):e47137. doi: 10.1371/journal.pone.0047137. Epub 2012 Oct 16.

Abstract

Determining the functional impact of somatic mutations is crucial to understanding tumorigenesis and metastasis. Recent sequences of several cancers have provided comprehensive lists of somatic mutations across entire genomes, enabling investigation of the functional impact of somatic mutations in non-coding regions. Here, we study somatic mutations in 3'UTRs of genes that have been identified in four cancers and computationally predict how they may alter miRNA targeting, potentially resulting in dysregulation of the expression of the genes harboring these mutations. We find that somatic mutations create or disrupt putative miRNA target sites in the 3'UTRs of many genes, including several genes, such as MITF, EPHA3, TAL1, SCG3, and GSDMA, which have been previously associated with cancer. We also integrate the somatic mutations with germline mutations and results of association studies. Specifically, we identify putative miRNA target sites in the 3'UTRs of BMPR1B, KLK3, and SPRY4 that are disrupted by both somatic and germline mutations and, also, are in linkage disequilibrium blocks with high scoring markers from cancer association studies. The somatic mutation in BMPR1B is located in a target site of miR-125b; germline mutations in this target site have previously been both shown to disrupt regulation of BMPR1B by miR-125b and linked with cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Base Sequence
  • Cell Transformation, Neoplastic / genetics
  • Genome-Wide Association Study
  • Germ-Line Mutation
  • Humans
  • Linkage Disequilibrium
  • MicroRNAs / genetics*
  • Mutation Rate
  • Mutation*
  • Neoplasm Metastasis / genetics
  • Neoplasms / genetics*
  • Neoplasms / pathology

Substances

  • 3' Untranslated Regions
  • MicroRNAs

Grant support

This work was partly supported by The University of Tennessee Center for Integrative and Translational Genomics. No additional external funding was received for this study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.