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

Oncogene volume 34, pages 2125–2137 (2015)Cite this article

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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.

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Acknowledgements

XC was supported by Lo Graduate Fellowship for Excellence in Stem Cell Research and a fellowship from the China Scholars Council. TP was supported by a donation from William Hyman, Yale College Class of 1980, in memory of Barbara Skydel. We thank I Tikhonova, M Mahajan and S Mane at the YCGA for performing the Nimblegen enrichment and Sequenom arrays. We thank M State for critical reading of this manuscript. This work was supported by a grant from an anonymous foundation.

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Author notes

  1. X Chen and T Paranjape: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA

    X Chen, C Stahlhut & F J Slack

  2. Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, CT, USA

    X Chen & H Zhao

  3. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA

    T Paranjape, S Nallur & J B Weidhaas

  4. Discipline of Surgery, National University of Ireland Galway and Galway University, Hospitals, Galway, Ireland

    T McVeigh, N Miller & M Kerin

  5. Yale University School of Medicine, New Haven, CT, USA

    F Keane

  6. Yale Center for Analytical Sciences, Yale University School of Medicine, New Haven, CT, USA

    Y Deng & X Yao

  7. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

    H Zhao

  8. Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA

    H Zhao

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Chen, X., Paranjape, T., Stahlhut, C. et al. Targeted resequencing of the microRNAome and 3′UTRome reveals functional germline DNA variants with altered prevalence in epithelial ovarian cancer. Oncogene 34, 2125–2137 (2015). https://doi.org/10.1038/onc.2014.117

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