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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 2014 Sep 04;33(36):4464-73 PMID: 24096489 PMCID: PMC4527534

Pubmed ID

24096489

DOI

10.1038/onc.2013.396

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.

Author List

Wilson IM, Vucic EA, Enfield KS, Thu KL, Zhang YA, Chari R, Lockwood WW, Radulovich N, Starczynowski DT, BanĂ¡th JP, Zhang M, Pusic A, Fuller M, Lonergan KM, Rowbotham D, Yee J, English JC, Buys TP, Selamat SA, Laird-Offringa IA, Liu P, Anderson M, You M, Tsao MS, Brown CJ, Bennewith KL, MacAulay CE, Karsan A, Gazdar AF, Lam S, Lam WL

Authors

Pengyuan Liu PhD Adjunct Associate Professor in the Physiology department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




Scopus

2-s2.0-84884967805   17 Citations

MESH terms used to index this publication - Major topics in bold

Carcinoma, Non-Small-Cell Lung
Chromosomes, Human, Pair 6
DNA Methylation
Epigenesis, Genetic
Gene Deletion
Gene Expression Regulation, Neoplastic
Gene Frequency
Gene Silencing
Genes, Tumor Suppressor
Genetic Association Studies
Genetic Variation
Genome, Human
Humans
Lung Neoplasms
Polymorphism, Single Nucleotide
Trans-Activators
Tumor Cells, Cultured
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e