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EYA4 is inactivated biallelically at a high frequency in sporadic lung cancer and is associated with familial lung cancer risk

Oncogene volume 33, pages 4464–4473 (2014)Cite this article

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Abstract

In an effort to identify novel biallelically inactivated tumor suppressor genes (TSGs) in sporadic invasive and preinvasive non-small-cell lung cancer (NSCLC) genomes, we applied a comprehensive integrated multiple ‘omics’ approach to investigate patient-matched, paired NSCLC tumor and non-malignant parenchymal tissues. By surveying lung tumor genomes for genes concomitantly inactivated within individual tumors by multiple mechanisms, and by the frequency of disruption in tumors across multiple cohorts, we have identified a putative lung cancer TSG, Eyes Absent 4 (EYA4). EYA4 is frequently and concomitantly deleted, hypermethylated and underexpressed in multiple independent lung tumor data sets, in both major NSCLC subtypes and in the earliest stages of lung cancer. We found that decreased EYA4 expression is not only associated with poor survival in sporadic lung cancers but also that EYA4 single-nucleotide polymorphisms are associated with increased familial cancer risk, consistent with EYA4s proximity to the previously reported lung cancer susceptibility locus on 6q. Functionally, we found that EYA4 displays TSG-like properties with a role in modulating apoptosis and DNA repair. Cross-examination of EYA4 expression across multiple tumor types suggests a cell-type-specific tumorigenic role for EYA4, consistent with a tumor suppressor function in cancers of epithelial origin. This work shows a clear role for EYA4 as a putative TSG in NSCLC.

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Acknowledgements

We thank Miwa Suzuki, Denise McDougal, Chad Malloff and Bradley Coe for assistance. Grant supports were from Canadian Institutes of Health Research (CIHR MOP86731, MOP77903, MOP94867), Canadian Cancer Society (CCS017076, CCS20485); Terry Fox Foundation (20395); NCI Early Detection Research Network (5U01 CA84971-10), Canary Foundation, NIH Genetic Epidemiology of Lung Cancer Consortium (U01CA76293); and scholarships from CIHR (IMW, EAV, KSSE and WWL) and Vanier Canada (RC, KLT and NR).

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Author notes

  1. I M Wilson and E A Vucic: These authors contributed equally to this work.

Authors and Affiliations

  1. Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada

    I M Wilson, E A Vucic, K S S Enfield, K L Thu, R Chari, W W Lockwood, J P Banáth, M Zhang, A Pusic, M Fuller, K M Lonergan, D Rowbotham, T P H Buys, K L Bennewith, C E MacAulay, A Karsan, S Lam & W L Lam

  2. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Y A Zhang & A F Gazdar

  3. Department of Genetics, Harvard Medical School, Boston, MA, USA

    R Chari

  4. National Human Genome Research Institute, Cancer Genetics Branch, Bethesda, MD, USA

    W W Lockwood

  5. Ontario Cancer Institute/Princess Margaret Hospital, Toronto, ON, Canada

    N Radulovich & M S Tsao

  6. Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH, USA

    D T Starczynowski

  7. Department of Surgery, Vancouver General Hospital, Vancouver, BC, Canada

    J Yee

  8. Department of Pathology, Vancouver General Hospital, Vancouver, BC, Canada

    J C English

  9. Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA

    S A Selamat & I A Laird-Offringa

  10. Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA

    P Liu, M Anderson & M You

  11. Department of Medical Genetics, University of British Columbia, Life Sciences Centre, Vancouver, BC, Canada

    C J Brown

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Correspondence to I M Wilson.

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Wilson, I., Vucic, E., Enfield, K. et al. EYA4 is inactivated biallelically at a high frequency in sporadic lung cancer and is associated with familial lung cancer risk. Oncogene 33, 4464–4473 (2014). https://doi.org/10.1038/onc.2013.396

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