Abstract 3110: The aging genome: Genetic mosaicism and its relationship to cancer
Authors: Jacobs Kevin B. , Yeager Meredith , Zhou Weiyin ,   DCEG Mosaicism Study Group (178 additional), Hoover Robert N. , Real Francisco X. , Fraumeni Joseph F. , Caporaso Neil E. , Tucker Margaret , Rothman Nathaniel , Pérez-Jurado Luis A. , Chanock Stephen J. 
Published: August 2012

Genetic mosaicism, the coexistence of cells of distinct genetic composition within an organism, has been associated with developmental and somatic disorders. Recently, we reported on 1,991 individuals from a population-based study of adult bladder cancer where we detected autosomal mosaicism in 1.7% of study subjects, suggesting a higher frequency than previously suspected, but did not reveal a significant association with bladder cancer. We have now extended our analysis to 57,853 subjects, 31,717 cancer cases and 26,136 cancer-free controls, using genome-wide SNP array data generated as part of 13 genome-wide association studies drawn from 48 case-control and case-cohort studies. Detection of autosomal mosaic events was based on assessment of allelic imbalance and copy number changes. We found autosomal mosaicism in blood or buccal mucosa DNA for chromosomal events of size &gt;2 Mb on 641 chromosomes in 517 individuals for an overall frequency of individuals with mosaicism of 0.87%. The most frequent type of event observed was copy-neutral LOH (48.2%), while copy-gains and copy-losses were observed for 15.1% and 34.8% of mosaic events, respectively. The strongest predictor of autosomal mosaicism was age at DNA collection. In cancer-free individuals, the frequency of having a mosaic event was 0.23% for those under 50 and 1.91% between 75 and 79 (p=4.8×10-8). Mosaicism was more frequent in males than females (OR=1.42, 1.14-1.80 95% CI, p=0.002) and in individuals with non-hematologic cancer (0.97% versus 0.74% in cancer-free individuals, OR=1.25, 1.04-1.50 95% CI, p=0.016), with a stronger association in cases who had DNA collected prior to treatment (OR=1.45, 1.18-1.80 95% CI, p=0.0005). Notable associations were observed in stratified analyses of lung (OR=1.56, 1.18-2.08 95% CI, p=0.002) and kidney (OR=1.98, 1.27-3.06 95% CI, p=0.002) cancers, both tobacco-associated malignancies. There was no significant association in non-hematological cancer cases overall between smoking (ever/never) and frequency of mosaicism (OR=1.19, 0.92-1.54 95% CI, p=0.19) or when stratified by cancer site. The frequency of mosaicism was higher in individuals diagnosed with leukemia who had DNA collected at least one year prior to diagnosis (overall OR=35.4, 14.7-76.6 95% CI, p=3.8×10-11); 15.8% had myeloid leukemia and 26.3% had lymphocytic leukemia. We conclude that autosomal mosaicism is present in the population with surprising frequency and particularly in the ageing genome. Further work is required to begin to unravel the underlying mechanisms, particularly as it relates to aging, the timing and expansion of distinct populations of cells bearing markedly different structural events in one or more chromosome. These findings underscore the importance of considering the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3110. doi:1538-7445.AM2012-3110