Targeted resequencing of the microRNAome and 3'UTRome reveals functional germline DNA variants with altered prevalence in epithelial ovarian cancer

Oncogene. 2015 Apr 16;34(16):2125-37. doi: 10.1038/onc.2014.117. Epub 2014 Jun 9.

Abstract

Ovarian cancer is a major cause of cancer deaths, yet there have been few known genetic risk factors identified, the best known of which are disruptions in protein coding sequences (BRCA1 and 2). Recent findings indicate that there are powerful genetic markers of cancer risk outside of these regions, in the noncoding mRNA control regions. To identify additional cancer-associated, functional non-protein-coding sequence germline variants associated with ovarian cancer risk, we captured DNA regions corresponding to all validated human microRNAs and the 3' untranslated regions (UTRs) of ~6000 cancer-associated genes from 31 ovarian cancer patients. Multiple single-nucleotide polymorphisms in the 3'UTR of the vascular endothelial growth factor receptor/FLT1, E2F2 and PCM1 oncogenes were highly enriched in ovarian cancer patients compared with the 1000 Genome Project. Sequenom validation in a case-control study (267 cases and 89 controls) confirmed a novel variant in the PCM1 3'UTR is significantly associated with ovarian cancer (P=0.0086). This work identifies a potential new ovarian cancer locus and further confirms that cancer resequencing efforts should not ignore the study of noncoding regions of cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Autoantigens / genetics*
  • Base Sequence
  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / genetics
  • Carcinoma, Ovarian Epithelial
  • Case-Control Studies
  • Cell Cycle Proteins / genetics*
  • DNA / genetics
  • E2F2 Transcription Factor / genetics
  • Female
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease
  • Humans
  • MicroRNAs / genetics
  • Neoplasms, Glandular and Epithelial / genetics*
  • Ovarian Neoplasms / genetics*
  • Polymorphism, Single Nucleotide
  • Receptors, Vascular Endothelial Growth Factor / genetics
  • Sequence Analysis, DNA
  • Vascular Endothelial Growth Factor Receptor-1 / genetics

Substances

  • 3' Untranslated Regions
  • Autoantigens
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • E2F2 Transcription Factor
  • E2F2 protein, human
  • Genetic Markers
  • MicroRNAs
  • PCM1 protein, human
  • DNA
  • FLT1 protein, human
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-1