Abstract 2757: Evaluation of EYA4 as a candidate risk locus in familial lung cancer families linked to 6q

Abstract

Abstract Recently, Wilson et al. (doi:10.1038/onc.2013.396) found that EYA4 was frequently inactivated biallelically in sporadic lung cancer, displays tumor suppressor gene-like properties and affects DNA repair, and that 5 of 17 common SNPs in this 0.3Mb region showed nominal association to familial lung cancer (FLC, p<0.05) although these associations are not genome-wide significant after correction for multiple testing.. However, this is an interesting candidate gene for FLC risk because it is located on chromosome 6q in a region where we previously showed evidence of linkage to FLC (PMID: 15272417, 20215501). Here, we sequenced 75 individuals from our 9 most strongly 6q-linked families, using Illumina technology and a custom Agilent kit to capture 37Mb of chromosome 6 from 130Mb to 167Mb. We closely examined a region around EYA4, between 133Mb and 135Mb. This region contains a number of other genes in addition to EYA4, including the Vanin cluster; ribosomal protein S12; the tumor suppressor gene TCF21 and its antisense RNA TARID which directs methylation and activation of TCF21; solute carriers SLC18B1 and SLC2A12 and the serum/glucocorticoid regulated kinase SGK1. To detect sharing of variants among affecteds in each family while allowing for phenocopies, singlepoint affected-only linkage analysis was performed on lung cancer affection status for all sequence variants using the Elston-Stewart algorithm implemented in the R package paramlink assuming penetrance of 0.01, 0.1 and 0.1 for dd/Dd/DD and a disease allele (D) frequency of 0.01, at a recombination fraction (theta) of 0. The highest total LOD score (summed over all 9 families) in the entire 37Mb targeted region was not near EYA4. In only one family was there any variant in EYA4 that appeared on the linked haplotype with close to the highest family-specific LOD score: Family 30 had a LOD of 0.6514 at several EYA4 variants (max LOD across region 0.6519). However, many variants across the region had similar LODs. In the remaining families, all EYA4 variants had LODs much lower than the maximum family-specific LOD score in the region. Thus, EYA4 variants are unlikely to explain our 6q linkage peak in these 6q-linked families. The second highest total LOD score for the entire 37Mb targeted region was found near EYA4 at 133.9Mb (LOD = 3.82), in the middle of the TARID antisense RNA gene. This variant appears to be entirely novel, as it is not present in any of the online variant databases, such as NHLBI's ESP or 1000 Genomes. In two families, the family LOD score at this locus was at or close to the highest in the region: in Family 44 the LOD score was 1.206 (max LOD across entire region 1.207) and in Family 35 the LOD score was 0.3958 (max LOD across region 0.3959). Therefore this variant in the TARID antisense RNA is a candidate in some of our families most strongly linked to chromosome 6q. Citation Format: Joan E. Bailey-Wilson, Claire L. Simpson, Susan M. Pinney, Mariza de Andrade, Colette Gaba, Ping Yang, Ming You, Elena Y. Kupert, Ann G. Schwartz, Diptasri Mandal, Christopher I. Amos, Marshall W. Anderson. Evaluation of EYA4 as a candidate risk locus in familial lung cancer families linked to 6q. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2757. doi:10.1158/1538-7445.AM2015-2757