Detectable clonal mosaicism and its relationship to aging and cancer.
Jacobs KB., Yeager M., Zhou W., Wacholder S., Wang Z., Rodriguez-Santiago B., Hutchinson A., Deng X., Liu C., Horner M-J., Cullen M., Epstein CG., Burdett L., Dean MC., Chatterjee N., Sampson J., Chung CC., Kovaks J., Gapstur SM., Stevens VL., Teras LT., Gaudet MM., Albanes D., Weinstein SJ., Virtamo J., Taylor PR., Freedman ND., Abnet CC., Goldstein AM., Hu N., Yu K., Yuan J-M., Liao L., Ding T., Qiao Y-L., Gao Y-T., Koh W-P., Xiang Y-B., Tang Z-Z., Fan J-H., Aldrich MC., Amos C., Blot WJ., Bock CH., Gillanders EM., Harris CC., Haiman CA., Henderson BE., Kolonel LN., Le Marchand L., McNeill LH., Rybicki BA., Schwartz AG., Signorello LB., Spitz MR., Wiencke JK., Wrensch M., Wu X., Zanetti KA., Ziegler RG., Figueroa JD., Garcia-Closas M., Malats N., Marenne G., Prokunina-Olsson L., Baris D., Schwenn M., Johnson A., Landi MT., Goldin L., Consonni D., Bertazzi PA., Rotunno M., Rajaraman P., Andersson U., Beane Freeman LE., Berg CD., Buring JE., Butler MA., Carreon T., Feychting M., Ahlbom A., Gaziano JM., Giles GG., Hallmans G., Hankinson SE., Hartge P., Henriksson R., Inskip PD., Johansen C., Landgren A., McKean-Cowdin R., Michaud DS., Melin BS., Peters U., Ruder AM., Sesso HD., Severi G., Shu X-O., Visvanathan K., White E., Wolk A., Zeleniuch-Jacquotte A., Zheng W., Silverman DT., Kogevinas M., Gonzalez JR., Villa O., Li D., Duell EJ., Risch HA., Olson SH., Kooperberg C., Wolpin BM., Jiao L., Hassan M., Wheeler W., Arslan AA., Bueno-de-Mesquita HB., Fuchs CS., Gallinger S., Gross MD., Holly EA., Klein AP., LaCroix A., Mandelson MT., Petersen G., Boutron-Ruault M-C., Bracci PM., Canzian F., Chang K., Cotterchio M., Giovannucci EL., Goggins M., Hoffman Bolton JA., Jenab M., Khaw K-T., Krogh V., Kurtz RC., McWilliams RR., Mendelsohn JB., Rabe KG., Riboli E., Tjønneland A., Tobias GS., Trichopoulos D., Elena JW., Yu H., Amundadottir L., Stolzenberg-Solomon RZ., Kraft P., Schumacher F., Stram D., Savage SA., Mirabello L., Andrulis IL., Wunder JS., Patiño García A., Sierrasesúmaga L., Barkauskas DA., Gorlick RG., Purdue M., Chow W-H., Moore LE., Schwartz KL., Davis FG., Hsing AW., Berndt SI., Black A., Wentzensen N., Brinton LA., Lissowska J., Peplonska B., McGlynn KA., Cook MB., Graubard BI., Kratz CP., Greene MH., Erickson RL., Hunter DJ., Thomas G., Hoover RN., Real FX., Fraumeni JF., Caporaso NE., Tucker M., Rothman N., Pérez-Jurado LA., Chanock SJ.
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.