Abstract 2542: Evidence for large somatic structural events detected as autosomal genetic mosaicism in GWAS data.

Abstract

Abstract Recent evidence indicates human mosaic abnormalities may be more common than previously expected. We performed an analysis on blood and buccal DNA of 30,918 individuals from a collection of 54 cancer-related studies using a modified mosaic alteration detection algorithm on renormalized B-allele frequencies and log2 relative probe intensity ratios from commercially available Illumina SNP microarray chips. 391 autosomal abnormalities >2Mb in size were detected in 232 (0.75%) individuals. The distribution includes copy-neutral loss of heterozygosity constituting 192 (49%) events, copy gains 85 (22%) events, and copy losses 102 (26%) events. There was no difference between blood and buccal sources of DNA. An overall analysis by age confirmed our earlier finding (p=8.93e-07), which was also observed in controls (p=0.0086). Similarly, an overall analysis by sex confirmed mosaic abnormalities are more frequent in males than females (p=0.0016); and this association was also observed in a control-only analysis (p=0.0019). Two or more distinct autosomal events were observed in 43 individuals. Comparable to earlier studies, the most common events were 4q copy neutral loss of heterozygosity, 9q copy neutral loss of heterozygosity, 13q14 deletion and 20q deletion. 13q14 deletion was observed in cancer-free controls and individuals with epithelial cancers. Cancer specific analyses for bladder, endometrium, stomach, lung (in nonsmoking women from Asia), osteosarcoma, and prostate cancer revealed no significant association with risk for cancer. These results replicate the prevalence and age/sex relationships from our previous findings in an analysis of 57,853 individuals and further suggest the importance of studying mosaic abnormalities in the general human population. The findings underscore the importance of thorough characterization of germline DNA in parallel with somatic characterization. Our results provide further support for age-related genomic senescence and could represent the tip of the iceberg for smaller somatic events. Citation Format: Mitchell J. Machiela, Weiyin Zhou, Meredith Yeager, Kevin Jacobs, Sonja Berndt, Qing Lan, Nathaniel Rothman, Sharon Savage, Phil R. Taylor, Immaculata deVivo, National Cancer Institute Detectable Clonal Mosaicism Consortium, Robert N. Hoover, Margaret A. Tucker, Stephen J. Chanock. Evidence for large somatic structural events detected as autosomal genetic mosaicism in GWAS data. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2542. doi:10.1158/1538-7445.AM2013-2542