Detectable Clonal Mosaicism and Its Relationship to Aging and Cancer

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.

Citing Articles

Clonal hematopoiesis: elements associated with clonal expansion and diseases.

Ryu G, Koh Y, Jaiswal S, Yoon S Blood Res. 2025; 60(1):17.

PMID: 40080235 PMC: 11906933. DOI: 10.1007/s44313-025-00065-7.

Epigenetic ageing clocks: statistical methods and emerging computational challenges.

Teschendorff A, Horvath S Nat Rev Genet. 2025; .

PMID: 39806006 DOI: 10.1038/s41576-024-00807-w.

A modeling of complex trait phenotypic variance determinants.

Hussain S PNAS Nexus. 2024; 3(11):pgae472.

PMID: 39529912 PMC: 11552524. DOI: 10.1093/pnasnexus/pgae472.

The Clinical Spectrum of Mosaic Genetic Disease.

Geiger H, Furuta Y, van Wyk S, Phillips 3rd J, Tinker R Genes (Basel). 2024; 15(10).

PMID: 39457364 PMC: 11507335. DOI: 10.3390/genes15101240.

Clonal hematopoiesis and hematological malignancy.

Dunn W, McLoughlin M, Vassiliou G J Clin Invest. 2024; 134(19).

PMID: 39352393 PMC: 11444162. DOI: 10.1172/JCI180065.

References

Pique-Regi R, Caceres A, Gonzalez J . R-Gada: a fast and flexible pipeline for copy number analysis in association studies. BMC Bioinformatics. 2010; 11:380. PMC: 2915992. DOI: 10.1186/1471-2105-11-380. View

Amary M, Damato S, Halai D, Eskandarpour M, Berisha F, Bonar F . Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet. 2011; 43(12):1262-5. DOI: 10.1038/ng.994. View

Snape K, Hanks S, Ruark E, Barros-NuneZ P, Elliott A, Murray A . Mutations in CEP57 cause mosaic variegated aneuploidy syndrome. Nat Genet. 2011; 43(6):527-9. PMC: 3508359. DOI: 10.1038/ng.822. View

Forsberg L, Rasi C, Razzaghian H, Pakalapati G, Waite L, Thilbeault K . Age-related somatic structural changes in the nuclear genome of human blood cells. Am J Hum Genet. 2012; 90(2):217-28. PMC: 3276669. DOI: 10.1016/j.ajhg.2011.12.009. View

Gurvich N, Perna F, Farina A, Voza F, Menendez S, Hurwitz J . L3MBTL1 polycomb protein, a candidate tumor suppressor in del(20q12) myeloid disorders, is essential for genome stability. Proc Natl Acad Sci U S A. 2010; 107(52):22552-7. PMC: 3012470. DOI: 10.1073/pnas.1017092108. View

Gonzalez J, Rodriguez-Santiago B, Caceres A, Pique-Regi R, Rothman N, Chanock S . A fast and accurate method to detect allelic genomic imbalances underlying mosaic rearrangements using SNP array data. BMC Bioinformatics. 2011; 12:166. PMC: 3118168. DOI: 10.1186/1471-2105-12-166. View

Benetatos L, Vartholomatos G, Hatzimichael E . MEG3 imprinted gene contribution in tumorigenesis. Int J Cancer. 2011; 129(4):773-9. DOI: 10.1002/ijc.26052. View

Pinto D, Darvishi K, Shi X, Rajan D, Rigler D, Fitzgerald T . Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants. Nat Biotechnol. 2011; 29(6):512-20. PMC: 3270583. DOI: 10.1038/nbt.1852. View

Pansuriya T, van Eijk R, dAdamo P, van Ruler M, Kuijjer M, Oosting J . Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet. 2011; 43(12):1256-61. PMC: 3427908. DOI: 10.1038/ng.1004. View

10.

Staaf J, Vallon-Christersson J, Lindgren D, Juliusson G, Rosenquist R, Hoglund M . Normalization of Illumina Infinium whole-genome SNP data improves copy number estimates and allelic intensity ratios. BMC Bioinformatics. 2008; 9:409. PMC: 2572624. DOI: 10.1186/1471-2105-9-409. View

11.

. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008; 455(7216):1061-8. PMC: 2671642. DOI: 10.1038/nature07385. View

12.

Hsu L, Kaffe S, Jenkins E, Alonso L, Benn P, David K . Proposed guidelines for diagnosis of chromosome mosaicism in amniocytes based on data derived from chromosome mosaicism and pseudomosaicism studies. Prenat Diagn. 1992; 12(7):555-73. DOI: 10.1002/pd.1970120702. View

13.

Tuna M, Knuutila S, Mills G . Uniparental disomy in cancer. Trends Mol Med. 2009; 15(3):120-8. DOI: 10.1016/j.molmed.2009.01.005. View

14.

Frio T, Lavoie J, Hamel N, Geyer F, Kushner Y, Novak D . Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia. N Engl J Med. 2010; 363(27):2628-37. DOI: 10.1056/NEJMoa1006565. View

15.

Solomon D, Kim T, Diaz-Martinez L, Fair J, Elkahloun A, Harris B . Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science. 2011; 333(6045):1039-43. PMC: 3374335. DOI: 10.1126/science.1203619. View

16.

Pekarsky Y, Zanesi N, Croce C . Molecular basis of CLL. Semin Cancer Biol. 2010; 20(6):370-6. PMC: 2997849. DOI: 10.1016/j.semcancer.2010.09.003. View

17.

Conlin L, Thiel B, Bonnemann C, Medne L, Ernst L, Zackai E . Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. Hum Mol Genet. 2010; 19(7):1263-75. PMC: 3146011. DOI: 10.1093/hmg/ddq003. View

18.

Marenne G, Rodriguez-Santiago B, Closas M, Perez-Jurado L, Rothman N, Rico D . Assessment of copy number variation using the Illumina Infinium 1M SNP-array: a comparison of methodological approaches in the Spanish Bladder Cancer/EPICURO study. Hum Mutat. 2010; 32(2):240-8. PMC: 3230937. DOI: 10.1002/humu.21398. View

19.

Peiffer D, Le J, Steemers F, Chang W, Jenniges T, Garcia F . High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping. Genome Res. 2006; 16(9):1136-48. PMC: 1557768. DOI: 10.1101/gr.5402306. View

20.

Rodriguez-Santiago B, Malats N, Rothman N, Armengol L, Garcia-Closas M, Kogevinas M . Mosaic uniparental disomies and aneuploidies as large structural variants of the human genome. Am J Hum Genet. 2010; 87(1):129-38. PMC: 2896781. DOI: 10.1016/j.ajhg.2010.06.002. View