Abstract
We sought to determine the significance of myeloid clonal hematopoiesis (CH) in the UK Biobank cohort (n = 502,524, median age = 58 years). Utilizing SNP array (n = 486,941) and whole exome sequencing data (n = 49,956), we identified 1166 participants with myeloid CH, defined by myeloid-associated mosaic chromosome abnormalities (mCA) and/or likely somatic driver mutations in DNMT3A, TET2, ASXL1, JAK2, SRSF2, or PPM1D. Myeloid CH increased by 1.1-fold per annum (myeloid mCA, P = 1.57 × 10−38; driver mutations, P = 5.89 × 10−47). Genome-wide association analysis identified two distinct signals within TERT that predisposed to myeloid CH, plus a weaker signal corresponding to the JAK2 46/1 haplotype. Specific subtypes of myeloid CH were associated with several blood features and clinical phenotypes, including TET2 mutations and chronic obstructive pulmonary disease. Smoking history was significantly associated with myeloid CH: 53% of myeloid CH cases were smokers compared to 44% of controls (P = 3.38 × 10−6), a difference principally due to current (OR = 1.10; P = 6.14 × 10−6) rather than past smoking (P = 0.08). Breakdown of CH by specific mutation type revealed that ASXL1 loss of function mutations were most strongly associated with current smoking status (OR = 1.07; P = 1.92 × 10−5), and the only abnormality associated with past smoking (OR = 1.04; P = 0.0026). We suggest that the inflammatory environment induced by smoking may promote the outgrowth of ASXL1-mutant clones.
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References
Busque L, Mio R, Mattioli J, Brais E, Blais N, Lalonde Y, et al. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood. 1996;88:59–65.
Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012;44:1179.
Xu X, Zhang Q, Luo J, Xing S, Li Q, Krantz SB, et al. JAK2V617F: prevalence in a large Chinese hospital population. Blood. 2007;109:339–42.
Laurie CC, Laurie CA, Rice K, Doheny KF, Zelnick LR, McHugh CP, et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet. 2012;44:642.
Jacobs KB, Yeager M, Zhou W, Wacholder S, Wang Z, Rodriguez-Santiago B, et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet. 2012;44:651.
Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477–87.
Zink F, Stacey SN, Norddahl GL, Frigge ML, Magnusson OT, Jonsdottir I, et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood. 2017;130:742–52.
Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.
Acuna-Hidalgo R, Sengul H, Steehouwer M, van de Vorst M, Vermeulen SH, Kiemeney LA, et al. Ultra-sensitive sequencing identifies high prevalence of clonal hematopoiesis-associated mutations throughout adult life. Am J Hum Genet. 2017;101:50–64.
Young AL, Challen GA, Birmann BM, Druley TE. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun. 2016;7:12484.
Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16.
Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377:111–21.
Buscarlet M, Provost S, Zada YF, Barhdadi A, Bourgoin V, Lépine G, et al. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood. 2017;130:753–62.
Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562:203.
Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, et al. Genome-wide genetic data on ~500,000 UK Biobank participants. BioRxiv. 2017. https://doi.org/10.1101/166298.
Staaf J, Lindgren D, Vallon-Christersson J, Isaksson A, Göransson H, Juliusson G, et al. Segmentation-based detection of allelic imbalance and loss-of-heterozygosity in cancer cells using whole genome SNP arrays. Genome Biol. 2008;9:R136.
Van Hout CV, Tachmazidou I, Backman JD, Hoffman JX, Yi B, Pandey A, et al. Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank. bioRxiv. 2019. https://doi.org/10.1101/572347.
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25:2078–9.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.
Hollander M, Wolfe DA, Chicken E. Nonparametric statistical methods, vol. 751. Hoboken, New Jersey: John Wiley & Sons; 2013.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.
Millard LA, Davies NM, Gaunt TR, Davey Smith G, Tilling K. Software application profile: PHESANT: a tool for performing automated phenome scans in UK Biobank. Int J Epidemiol. 2017;47:29–35.
Therneau TM, Grambsch PM. The Cox model. Modeling survival data: extending the Cox model. New York: Springer; 2000, pp. 39–77.
Grolemund G, Wickham H. Dates and times made easy with lubridate. J Stat Softw. 2011;40:1–25.
Roman E, Smith A, Appleton S, Crouch S, Kelly R, Kinsey S, et al. Myeloid malignancies in the real-world: Occurrence, progression and survival in the UK’s population-based Haematological Malignancy Research Network 2004–15. Cancer Epidemiol. 2016;42:186–98.
McKerrell T, Park N, Moreno T, Grove CS, Ponstingl H, Stephens J, et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 2015;10:1239–45.
Jones AV, Chase A, Silver RT, Oscier D, Zoi K, Wang YL, et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet. 2009;41:446–9.
Bolton KL, Ptashkin RN, Gao T, Braunstein L, Devlin SM, Kelly D, et al. Oncologic therapy shapes the fitness landscape of clonal hematopoiesis. bioRxiv. 2019. https://doi.org/10.1101/848739.
Gillis NK, Ball M, Zhang Q, Ma Z, Zhao Y, Yoder SJ, et al. Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol. 2017;18:112–21.
Coombs CC, Zehir A, Devlin SM, Kishtagari A, Syed A, Jonsson P, et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell. 2017;21:374–82.
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.
Hinds DA, Barnholt KE, Mesa RA, Kiefer AK, Do CB, Eriksson N, et al. Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood, J Am Soc Hematol. 2016;128:1121–8.
Oddsson A, Kristinsson S, Helgason H, Gudbjartsson D, Masson G, Sigurdsson A, et al. The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms. Leukemia. 2014;28:1371–4.
Tapper W, Jones AV, Kralovics R, Harutyunyan AS, Zoi K, Leung W, et al. Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. Nat Commun. 2015;6:1–11.
Liu N, Guo XH, Liu JP, Cong YS. Role of telomerase in the tumour microenvironment. Clin Exp Pharmacol Physiol. 2019;47:357–64.
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AAZD was supported by Lady Tata International Award; NCPC was supported by Blood Cancer UK.
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Dawoud, A.A.Z., Tapper, W.J. & Cross, N.C.P. Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking. Leukemia 34, 2660–2672 (2020). https://doi.org/10.1038/s41375-020-0896-8
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DOI: https://doi.org/10.1038/s41375-020-0896-8
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