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
Date
10/08/2013Pubmed ID
24096489Pubmed Central ID
PMC4527534DOI
10.1038/onc.2013.396Scopus ID
2-s2.0-84884967805 (requires institutional sign-in at Scopus site) 39 CitationsAbstract
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, Banáth 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 WLMESH terms used to index this publication - Major topics in bold
Carcinoma, Non-Small-Cell LungChromosomes, 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
