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Oncogene. 2014 Sep 4;33(36):4464-73. doi: 10.1038/onc.2013.396. Epub 2013 Oct 7.

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

Author information

  • 1Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
  • 2Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 31] Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada [2] Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • 41] Integrative Oncology Genetics Unit, British Columbia Cancer Research Centre, Vancouver, BC, Canada [2] National Human Genome Research Institute, Cancer Genetics Branch, Bethesda, MD, USA.
  • 5Ontario Cancer Institute/Princess Margaret Hospital, Toronto, ON, Canada.
  • 6Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
  • 7Department of Surgery, Vancouver General Hospital, Vancouver, BC, Canada.
  • 8Department of Pathology, Vancouver General Hospital, Vancouver, BC, Canada.
  • 9Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA.
  • 10Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA.
  • 11Department of Medical Genetics, University of British Columbia, Life Sciences Centre, Vancouver, BC, Canada.


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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