Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Germline risk of clonal haematopoiesis

Nature Reviews Genetics volume 22, pages 603–617 (2021)Cite this article

Subjects

A Publisher Correction to this article was published on 17 June 2021

This article has been updated

Abstract

Clonal haematopoiesis (CH) is a common, age-related expansion of blood cells with somatic mutations that is associated with an increased risk of haematological malignancies, cardiovascular disease and all-cause mortality. CH may be caused by point mutations in genes associated with myeloid neoplasms, chromosomal copy number changes and loss of heterozygosity events. How inherited and environmental factors shape the incidence of CH is incompletely understood. Even though the several varieties of CH may have distinct phenotypic consequences, recent research points to an underlying genetic architecture that is highly overlapping. Moreover, there are numerous commonalities between the inherited variation associated with CH and that which has been linked to age-associated biomarkers and diseases. In this Review, we synthesize what is currently known about how inherited variation shapes the risk of CH and how this genetic architecture intersects with the biology of diseases that occur with ageing.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Types of clonal haematopoiesis.
Fig. 2: CH subtypes have shared and unique risk variants.
Fig. 3: CHIP has polygenic risk.
Fig. 4: Using germline variation to study causal associations of CH.

Similar content being viewed by others

Change history

References

  1. Orkin, S. H. & Zon, L. I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631–644 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lee-Six, H. et al. Population dynamics of normal human blood inferred from somatic mutations. Nature 561, 473–478 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Beerman, I. et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc. Natl Acad. Sci. USA 107, 5465–5470 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Welch, J. S. et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 150, 264–278 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jan, M., Ebert, B. L. & Jaiswal, S. Clonal hematopoiesis. Semin. Hematol. 54, 43–50 (2017).

    Article  PubMed  Google Scholar 

  6. Busque, L. et al. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 88, 59–65 (1996). This paper, showing age-associated chromosome X inactivation skew, provided the initial evidence that was suggestive of clonality in the blood of individuals without haematological disease.

    Article  CAS  PubMed  Google Scholar 

  7. Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014). This work was the first to find associations between non-cancer mortality and CHIP.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014). This study delineated CH from unknown drivers and the strong association between CHIP and leukaemia.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Loh, P.-R. et al. Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Nature 559, 350–355 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zink, F. et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742–752 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Thompson, D. J. et al. Genetic predisposition to mosaic Y chromosome loss in blood. Nature 575, 652–657 (2019). This study on the genetic determinants of mLOY is the largest to date and used multiple modalities to validate associations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kakiuchi, N. & Ogawa, S. Clonal expansion in non-cancer tissues. Nat. Rev. Cancer 21, 239–256 (2021). This recent review presents the current knowledge regarding clonality throughout the human body and is a good entry point for those seeking to learn more about the field.

    Article  CAS  PubMed  Google Scholar 

  13. Wright, D. J. et al. Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility. Nat. Genet. 49, 674–679 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhou, W. et al. Mosaic loss of chromosome Y is associated with common variation near TCL1A. Nat. Genet. 48, 563–568 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Loftfield, E. et al. Predictors of mosaic chromosome Y loss and associations with mortality in the UK Biobank. Sci. Rep. 8, 12316 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Dumanski, J. P. et al. Smoking is associated with mosaic loss of chromosome Y. Science 347, 81–83 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Loh, P.-R., Genovese, G. & McCarroll, S. A. Monogenic and polygenic inheritance become instruments for clonal selection. Nature 584, 136–141 (2020). This large study of mCA genetics found that both monogenic and polygenic risk variants can predict mCA events.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

  19. Young, A. L., Challen, G. A., Birmann, B. M. & Druley, T. E. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7, 12484 (2016). This paper measuring somatic mutations down to very low allele burden found acquired variants in the blood of 95% (19/20) of sampled adults.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Watson, C. J. et al. The evolutionary dynamics and fitness landscape of clonal hematopoiesis. Science 367, 1449–1454 (2020).

    Article  CAS  PubMed  Google Scholar 

  21. Forsberg, L. A. et al. Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer. Nat. Genet. 46, 624–628 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhou, W. et al. Detectable chromosome X mosaicism in males is rarely tolerated in peripheral leukocytes. Sci. Rep. 11, 1193 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jacobs, K. B. et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat. Genet. 44, 651–658 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Machiela, M. J. et al. Characterization of large structural genetic mosaicism in human autosomes. Am. J. Hum. Genet. 96, 487–497 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Laurie, C. C. et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat. Genet. 44, 642–650 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Terao, C. et al. Chromosomal alterations among age-related haematopoietic clones in Japan. Nature 584, 130–135 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bick, A. G. et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 586, 763–768 (2020). This study is the largest GWAS of CHIP done to date.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Perner, F., Perner, C., Ernst, T. & Heidel, H. F. Roles of JAK2 in aging, inflammation, hematopoiesis and malignant transformation. Cells 8, 854 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  29. Kralovics, R. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–1790 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Gao, T. et al. Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis. Nat. Commun. 12, 338 (2021). This study was the first to examine the combined effect of CHIP and mCAs on patient outcomes, finding increased mortality in individuals with both types of lesions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. McKerrell, T. et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 10, 1239–1245 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Coombs, C. C. et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 21, 374–382.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Loftfield, E. et al. Mosaic Y loss is moderately associated with solid tumor risk. Cancer Res. 79, 461 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Lin, S.-H. et al. Mosaic chromosome Y loss is associated with alterations in blood cell counts in UK Biobank men. Sci. Rep. 10, 3655 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bolton, K. L. et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat. Genet. 52, 1219–1226 (2020). This paper offers a detailed look at how radiotherapy, chemotherapy, targeted agents and immune therapies are associated with CHIP.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Boucai, L. et al. Radioactive iodine-related clonal hematopoiesis in thyroid cancer is common and associated with decreased survival. J. Clin. Endocrinol. Metab. 103, 4216–4223 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Pich, O. et al. The evolution of hematopoietic cells under cancer therapy. bioRxiv https://doi.org/10.1101/2020.10.29.360230 (2020).

    Article  Google Scholar 

  38. Ganster, C. et al. New data shed light on Y-loss-related pathogenesis in myelodysplastic syndromes. Genes Chromosomes Cancer 54, 717–724 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Noveski, P. et al. Loss of Y chromosome in peripheral blood of colorectal and prostate cancer patients. PLoS ONE 11, e0146264 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Machiela, M. J. et al. Mosaic chromosome Y loss and testicular germ cell tumor risk. J. Hum. Genet. 62, 637–640 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Haitjema, S. et al. Loss of Y chromosome in blood is associated with major cardiovascular events during follow-up in men after carotid endarterectomy. Circ. Cardiovasc. Genet. 10, e001544 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Dumanski, J. P. et al. Mosaic loss of chromosome Y in blood is associated with Alzheimer disease. Am. J. Hum. Genet. 98, 1208–1219 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hirata, T. et al. Investigation of chromosome Y loss in men with schizophrenia. Neuropsychiatr. Dis. Treat. 14, 2115–2122 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Persani, L. et al. Increased loss of the Y chromosome in peripheral blood cells in male patients with autoimmune thyroiditis. J. Autoimmun. 38, J193–J196 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Lleo, A. et al. Y chromosome loss in male patients with primary biliary cirrhosis. J. Autoimmun. 41, 87–91 (2013).

    Article  PubMed  Google Scholar 

  46. Grassmann, F. et al. Y chromosome mosaicism is associated with age-related macular degeneration. Eur. J. Hum. Genet. 27, 36–41 (2019).

    Article  CAS  PubMed  Google Scholar 

  47. Zekavat, S. M. et al. Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer. medRxiv https://doi.org/10.1101/2020.11.12.20230821 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Abelson, S. et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 559, 400–404 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Desai, P. et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat. Med. 24, 1015–1023 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 337, 111–121 (2017).

    Article  Google Scholar 

  51. Bick, A. G. et al. Genetic interleukin 6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis. Circulation 141, 124–131 (2020). This paper was the first to examine how inherited germline variation can alter the clinical consequences of CHIP, finding lower rates of cardiovascular events in individuals with CHIP and a germline polymorphism attenuating IL-6 receptor signalling compared to those without the polymorphism.

    Article  CAS  PubMed  Google Scholar 

  52. Honigberg, M. C. et al. Premature menopause, clonal hematopoiesis, and coronary artery disease in postmenopausal women. Circulation 143, 410–423 (2021).

    Article  PubMed  Google Scholar 

  53. Busque, L. et al. High-sensitivity C-reactive protein is associated with clonal hematopoiesis of indeterminate potential. Blood Adv. 4, 2430–2438 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fuster, J. J. et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang, W. et al. Macrophage inflammation, erythrophagocytosis and accelerated atherosclerosis in Jak2V617F Mice. Circ. Res. 11, e35–e47 (2018).

    Google Scholar 

  56. Sano, S. et al. Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome. J. Am. Coll. Cardiol. 71, 875–886 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sano, S. et al. JAK2V617F-mediated clonal hematopoiesis accelerates pathological remodeling in murine heart failure. JACC 4, 684–697 (2019).

    PubMed  PubMed Central  Google Scholar 

  58. Lyko, F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat. Rev. Genet. 19, 81–92 (2018).

    Article  CAS  PubMed  Google Scholar 

  59. Zhang, Q. et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389–393 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Poisson, J. et al. Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm. J. Clin. Invest. 130, 2630–2643 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wolach, O. et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci. Transl. Med. 10, eaan8292 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Buscarlet, M. et al. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130, 753–762 (2017).

    Article  CAS  PubMed  Google Scholar 

  63. Miller, P. et al. Contribution of clonal hematopoiesis to adult-onset hemophagocytic lymphohistiocytosis. Blood 136, 3051–3055 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Arends, C. M. et al. Clonal hematopoiesis in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Haematologica 105, e264–e267 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Bolton, K. L. et al. Clonal hematopoiesis is associated with risk of severe Covid-19. medRxiv https://doi.org/10.1101/2020.11.25.20233163 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Abplanalp, W. T. et al. Association of clonal hematopoiesis of indeterminate potential with inflammatory gene expression in patients with severe degenerative aortic valve stenosis or chronic postischemic heart failure. JAMA Cardiol. 5, 1170–1175 (2020).

    Article  PubMed  Google Scholar 

  67. Bick, A. G. et al. Increased CHIP Prevalence Amongst People Living with HIV. medRxiv https://doi.org/10.1101/2020.11.06.20225607 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Dharan, N. J. et al. Age-related clonal haematopoiesis is more prevalent in older adults with HIV: the ARCHIVE study. medRxiv https://doi.org/10.1101/2020.11.19.20235069 (2020).

    Article  Google Scholar 

  69. Takahashi, K. et al. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol. 18, 100–111 (2017).

    Article  PubMed  Google Scholar 

  70. Lindsley, R. C. et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N. Engl. J. Med. 376, 536–547 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kahn, J. D. et al. PPM1D truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood 132, 1095–1105 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hsu, J. I. et al. PPM1D mutations drive clonal hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell 23, 700–713.e706 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mas-Peiro, S. et al. Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation. Eur. Heart J. 41, 933–939 (2019).

    Article  PubMed Central  CAS  Google Scholar 

  74. Nawas, M. T. et al. The clinical implications of clonal hematopoiesis in hematopoietic cell transplantation. Blood Rev. 46, 100744 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Wilk, C. M., Manz, M. G. & Boettcher, S. Clonal hematopoiesis in hematopoietic stem cell transplantation. Curr. Opin. Hematol. 28, 94–100 (2021).

    Article  CAS  PubMed  Google Scholar 

  76. Steensma, D. P. et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126, 9–16 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sperling, A. S., Gibson, C. J. & Ebert, B. L. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat. Rev. Cancer 17, 5–19 (2017).

    Article  CAS  PubMed  Google Scholar 

  78. Bao, E. L. et al. Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells. Nature 586, 769–775 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hinds, D. A. et al. Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood 128, 1121–1128 (2016). This large study of individuals with JAK2 mutations found several strong germline associations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Vardiman, J. W. et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114, 937 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Arber, D. A. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127, 2391–2405 (2016).

    Article  CAS  PubMed  Google Scholar 

  82. Jones, A. V. et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat. Genet. 41, 446–449 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kilpivaara, O. et al. A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms. Nat. Genet. 41, 455–459 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Olcaydu, D. et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat. Genet. 41, 450–454 (2009). Jones et al.82, Kilpivaara et al.83 and Olcaydu et al.84 identified variation in the 46/1 haplotype as linked to MPNs.

    Article  CAS  PubMed  Google Scholar 

  85. Trifa, A. P. et al. The G allele of the JAK2 rs10974944 SNP, part of JAK2 46/1 haplotype, is strongly associated with JAK2 V617F-positive myeloproliferative neoplasms. Ann. Hematol. 89, 979–983 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Trifa, A. P. et al. TERT rs2736100 A>C SNP and JAK2 46/1 haplotype significantly contribute to the occurrence of JAK2 V617F and CALR mutated myeloproliferative neoplasms – a multicentric study on 529 patients. Br. J. Haematol. 174, 218–226 (2016).

    Article  CAS  PubMed  Google Scholar 

  87. Trifa, A. P. et al. MECOM, HBS1L-MYB, THRB-RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: a study on 939 patients. Am. J. Hematol. 93, 100–106 (2018).

    Article  CAS  PubMed  Google Scholar 

  88. Tapper, W. et al. Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. Nat. Commun. 6, 6691 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Oddsson, A. et al. The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms. Leukemia 28, 1371–1374 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. McKerrell, T. et al. JAK2 V617F hematopoietic clones are present several years prior to MPN diagnosis and follow different expansion kinetics. Blood Adv. 1, 968–971 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Shay, J. W. & Wright, W. E. Telomeres and telomerase: three decades of progress. Nat. Rev. Genet. 20, 299–309 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Zimmermann, S. & Martens, U. M. Telomeres, senescence, and hematopoietic stem cells. Cell Tissue Res. 331, 79–90 (2008).

    Article  PubMed  Google Scholar 

  93. Akada, H. et al. Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells. Stem Cells 32, 1878–1889 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Allsopp, R. C., Morin, G. B., DePinho, R., Harley, C. B. & Weissman, I. L. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 102, 517–520 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Gery, S. & Koeffler, H. P. Role of the adaptor protein LNK in normal and malignant hematopoiesis. Oncogene 32, 3111–3118 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Moran-Crusio, K. et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20, 11–24 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. van der Meer, L. T., Jansen, J. H. & van der Reijden, B. A. Gfi1 and Gfi1b: key regulators of hematopoiesis. Leukemia 24, 1834–1843 (2010).

    Article  PubMed  CAS  Google Scholar 

  99. Ichikawa, M. et al. AML1/Runx1 negatively regulates quiescent hematopoietic stem cells in adult hematopoiesis. J. Immunol. 180, 4402–4408 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Churpek, J. E. et al. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood 126, 2484–2490 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Brown, A. L. et al. RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. Blood Adv. 4, 1131–1144 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Mangaonkar, A. A. & Patnaik, M. M. Hereditary predisposition to hematopoietic neoplasms: when bloodline matters for blood cancers. Mayo Clin. Proc. 95, 1482–1498 (2020).

    Article  CAS  PubMed  Google Scholar 

  103. Fabre, M. A. et al. Concordance for clonal hematopoiesis is limited in elderly twins. Blood 135, 269–273 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Hansen, J. W. et al. Clonal hematopoiesis in elderly twins: concordance, discordance, and mortality. Blood 135, 261–268 (2020). Fabre et al.103 and Hansen et al.104 are the first studies examining the prevalence of CHIP among twin pairs; these papers also provided the first evidence suggesting some CHIP mutations may be acquired in utero.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Williams, N. et al. Phylogenetic reconstruction of myeloproliferative neoplasm reveals very early origins and lifelong evolution. bioRxiv https://doi.org/10.1101/2020.11.09.374710 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Van Egeren, D. et al. Reconstructing the lineage histories and differentiation trajectories of individual cancer cells in myeloproliferative neoplasms. Cell Stem Cell 28, 514–523.e9 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Terao, C. et al. GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation. Nat. Commun. 10, 4719 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Laine, J., Künstle, G., Obata, T., Sha, M. & Noguchi, M. The protooncogene TCL1 Is an Akt kinase coactivator. Mol. Cell 6, 395–407 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Virgilio, L. et al. Deregulated expression of TCL1 causes T cell leukemia in mice. Proc. Natl Acad. Sci. USA 95, 3885–3889 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Nagai, A. et al. Overview of the BioBank Japan Project: Study design and profile. J. Epidemiol. 27 (Suppl. 3), S2–S8 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Madani, N. et al. Implication of the lymphocyte-specific nuclear body protein Sp140 in an innate response to human immunodeficiency virus type 1. J. Virol. 76, 11133–11138 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Li, L., Forman, S. J. & Bhatia, R. Expression of DLK1 in hematopoietic cells results in inhibition of differentiation and proliferation. Oncogene 24, 4472–4476 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Koren, A. et al. Genetic variation in human DNA replication timing. Cell 159, 1015–1026 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Landau, D. A. et al. Mutations driving CLL and their evolution in progression and relapse. Nature 526, 525–530 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Puente, X. S. et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519–524 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Tamura, K. et al. Chronic lymphocytic leukemia (CLL) is rare, but the proportion of T-CLL is high in Japan. Eur. J. Haematol. 67, 152–157 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. Ben-Eghan, C. et al. Don’t ignore genetic data from minority populations. Nature 585, 184–186 (2020).

    Article  CAS  PubMed  Google Scholar 

  119. Taliun, D. et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature 590, 290–299 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bell, D. W. et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286, 2528 (1999).

    Article  CAS  PubMed  Google Scholar 

  121. Vahteristo, P. et al. p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 61, 5718–5722 (2001).

    CAS  PubMed  Google Scholar 

  122. Siddiqui, R. et al. The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds. Fam. Cancer 4, 177–181 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Ruijs, M. W. et al. The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype. Hered. Cancer Clin. Pract. 7, 4 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Manoukian, S. et al. Two new CHEK2 germ-line variants detected in breast cancer/sarcoma families negative for BRCA1, BRCA2, and TP53 gene mutations. Breast Cancer Res. Treat. 130, 207–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).

    Article  CAS  PubMed  Google Scholar 

  126. Chompret, A. et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br. J. Cancer 82, 1932–1937 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Gonzalez, K. D. et al. Beyond Li fraumeni syndrome: clinical characteristics of families With p53 germline mutations. J. Clin. Oncol. 27, 1250–1256 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Carney, J. P. et al. The hMre11/hRad50 protein complex and nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93, 477–486 (1998).

    Article  CAS  PubMed  Google Scholar 

  129. Varon, R. et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in nijmegen breakage syndrome. Cell 93, 467–476 (1998).

    Article  CAS  PubMed  Google Scholar 

  130. Bartkova, J. et al. Aberrations of the MRE11–RAD50–NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene. Mol. Oncol. 2, 296–316 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Belhadj, S. et al. Candidate genes for hereditary colorectal cancer: mutational screening and systematic review. Hum. Mutat. 41, 1563–1576 (2020).

    Article  CAS  PubMed  Google Scholar 

  132. Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749–1753 (1995).

    Article  CAS  PubMed  Google Scholar 

  133. Suarez, F. et al. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies. J. Clin. Oncol. 33, 202–208 (2015).

    Article  PubMed  Google Scholar 

  134. Reiman, A. et al. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. Br. J. Cancer 105, 586–591 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Swift, M., Morrell, D., Massey, R. B. & Chase, C. L. Incidence of cancer in 161 families affected by ataxia–telangiectasia. N. Engl. J. Med. 325, 1831–1836 (1991).

    Article  CAS  PubMed  Google Scholar 

  136. Thompson, D. et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J. Natl Cancer Inst. 97, 813–822 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. Lu, C. et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat. Commun. 6, 10086 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. Angèle, S. et al. ATM polymorphisms as risk factors for prostate cancer development. Br. J. Cancer 91, 783–787 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Medina, R. et al. The HiNF-P/p220NPAT cell cycle signaling pathway controls nonhistone target genes. Cancer Res. 67, 10334–10342 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. Saarinen, S. et al. Exome sequencing reveals germline NPAT mutation as a candidate risk factor for Hodgkin lymphoma. Blood 118, 493–498 (2011).

    Article  CAS  PubMed  Google Scholar 

  141. Duployez, N. et al. Familial myeloid malignancies with germline TET2 mutation. Leukemia 34, 1450–1453 (2020).

    Article  PubMed  Google Scholar 

  142. Stremenova Spegarova, J. et al. Germline TET2 loss of function causes childhood immunodeficiency and lymphoma. Blood 136, 1055–1066 (2020).

    Article  PubMed  Google Scholar 

  143. Kaasinen, E. et al. Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans. Nat. Commun. 10, 1252 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Maslah, N., Cassinat, B., Verger, E., Kiladjian, J. J. & Velazquez, L. The role of LNK/SH2B3 genetic alterations in myeloproliferative neoplasms and other hematological disorders. Leukemia 31, 1661–1670 (2017).

    Article  CAS  PubMed  Google Scholar 

  145. Kuo, C.-L. et al. The longevity-associated SH2B3 (LNK) genetic variant: selected aging phenotypes in 379,758 subjects. J. Gerontol. 75, 1656–1662 (2020).

    Article  CAS  Google Scholar 

  146. Hung, R. J. et al. Cross cancer genomic investigation of inflammation pathway for five common cancers: lung, ovary, prostate, breast, and colorectal cancer. J. Natl Cancer Inst. 107, djv246 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Wang, Y. et al. Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction. JCI Insight 5, e135204 (2020).

    Article  PubMed Central  Google Scholar 

  148. Potus, F. et al. Novel mutations and decreased expression of the epigenetic regulator TET2 in pulmonary arterial hypertension. Circulation 141, 1986–2000 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Ko, M. et al. Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc. Natl Acad. Sci. USA 108, 14566–14571 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Li, Z. et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118, 4509–4518 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Quivoron, C. et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20, 25–38 (2011).

    Article  CAS  PubMed  Google Scholar 

  152. Pan, F. et al. Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells. Nat. Commun. 8, 15102 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Levy, D. et al. Genome-wide association study of blood pressure and hypertension. Nat. Genet. 41, 677–687 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Newton-Cheh, C. et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat. Genet. 41, 666–676 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Laroumanie, F. et al. LNK deficiency promotes acute aortic dissection and rupture. JCI Insight 3, e122558 (2018).

    Article  PubMed Central  Google Scholar 

  156. Safarova Maya, S. et al. Targeted sequencing study to uncover shared genetic susceptibility between peripheral artery disease and coronary heart disease — brief report. Arterioscler. Thromb. Vasc. Biol. 39, 1227–1233 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Dichgans, M. et al. Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. Stroke 45, 24–36 (2014).

    Article  CAS  PubMed  Google Scholar 

  158. Demanelis, K. et al. Determinants of telomere length across human tissues. Science 369, eaaz6876 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Hosokawa, K. & Arai, F. The role of telomere binding molecules for normal and abnormal hematopoiesis. Int. J. Hematol. 107, 646–655 (2018).

    Article  CAS  PubMed  Google Scholar 

  160. Bojesen, S. E. et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat. Genet. 45, 371–384 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Melin, B. S., Nordfjäll, K., Andersson, U. & Roos, G. hTERT cancer risk genotypes are associated with telomere length. Genet. Epidemiol. 36, 368–372 (2012).

    Article  PubMed  Google Scholar 

  162. Brown, D. W. et al. Genetically predicted telomere length is associated with clonal somatic copy number alterations in peripheral leukocytes. PLoS Genet. 16, e1009078 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Nakao, T. et al. Bidirectional Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of intermediate potential. medRxiv https://doi.org/10.1101/2021.02.26.21252199 (2021).

    Article  Google Scholar 

  164. McNally, E. J., Luncsford, P. J. & Armanios, M. Long telomeres and cancer risk: the price of cellular immortality. J. Clin. Invest. 129, 3474–3481 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Han, H. et al. Association of TERT polymorphisms and risk of coronary heart disease in a Chinese Han population. Oncotarget 8, 67519–67525 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Bressler, J. et al. Sequence variation in telomerase reverse transcriptase (TERT) as a determinant of risk of cardiovascular disease: the Atherosclerosis Risk in Communities (ARIC) study. BMC Med. Genet. 16, 52 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Codd, V. et al. Identification of seven loci affecting mean telomere length and their association with disease. Nat. Genet. 45, 422–427 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Maubaret, C. G. et al. Association of TERC and OBFC1 haplotypes with mean leukocyte telomere length and risk for coronary heart disease. PLoS ONE 8, e83122 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018). This review provides a nuanced overview of epigenetic clocks.

    Article  CAS  PubMed  Google Scholar 

  170. Robertson, N. A. et al. Age-related clonal haemopoiesis is associated with increased epigenetic age. Curr. Biol. 29, R786–R787 (2019).

    Article  CAS  PubMed  Google Scholar 

  171. McCartney, D. L. et al. Genome-wide association studies identify 137 loci for DNA methylation biomarkers of ageing. bioRxiv https://doi.org/10.1101/2020.06.29.133702 (2020).

    Article  Google Scholar 

  172. Lu, A. T. et al. GWAS of epigenetic aging rates in blood reveals a critical role for TERT. Nat. Commun. 9, 387 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Izzo, F. et al. DNA methylation disruption reshapes the hematopoietic differentiation landscape. Nat. Genet. 52, 378–387 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Bowman, R. L., Busque, L. & Levine, R. L. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell 22, 157–170 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Davey Smith, G. & Hemani, G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum. Mol. Genet. 23, R89–R98 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Holmes, M. V., Ala-Korpela, M. & Smith, G. D. Mendelian randomization in cardiometabolic disease: challenges in evaluating causality. Nat. Rev. Cardiol. 14, 577–590 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Bolton, K. L. et al. The clinical management of clonal hematopoiesis: creation of a clonal hematopoiesis clinic. Hematol. Oncol. Clin. North Am. 34, 357–367 (2020). This paper describes a new type of clinic that focuses on patients with CH.

    Article  PubMed  Google Scholar 

  178. Scheller Madrid, A. et al. Observational and genetic studies of short telomeres and Alzheimer’s disease in 67,000 and 152,000 individuals: a Mendelian randomization study. Eur. J. Epidemiol. 35, 147–156 (2020).

    Article  CAS  PubMed  Google Scholar 

  179. Roake, C. M. & Artandi, S. E. Regulation of human telomerase in homeostasis and disease. Nat. Rev. Mol. Cell Biol. 21, 384–397 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Yeh, J.-K. & Wang, C.-Y. Telomeres and telomerase in cardiovascular diseases. Genes 7, 58 (2016).

    Article  PubMed Central  CAS  Google Scholar 

  181. Boccardi, V., Pelini, L., Ercolani, S., Ruggiero, C. & Mecocci, P. From cellular senescence to Alzheimer’s disease: the role of telomere shortening. Ageing Res. Rev. 22, 1–8 (2015).

    Article  CAS  PubMed  Google Scholar 

  182. Herrmann, M., Pusceddu, I., März, W. & Herrmann, W. Telomere biology and age-related diseases. Clin. Chem. Lab. Med. 56, 1210–1222 (2018).

    Article  CAS  PubMed  Google Scholar 

  183. Wu, X., Dong, X., Liu, W. & Chen, J. Characterization of CHEK2 mutations in prostate cancer. Hum. Mutat. 27, 742–747 (2006).

    Article  CAS  PubMed  Google Scholar 

  184. Nanda, N. & Roberts, N. J. ATM serine/threonine kinase and its role in pancreatic risk. Genes 11, 108 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  185. Teitell, M. A. The TCL1 family of oncoproteins: co-activators of transformation. Nat. Rev. Cancer 5, 640–648 (2005).

    Article  CAS  PubMed  Google Scholar 

  186. Lio, C.-W. J., Yuita, H. & Rao, A. Dysregulation of the TET family of epigenetic regulators in lymphoid and myeloid malignancies. Blood 134, 1487–1497 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Ryan, S. D. et al. Up-regulation of the mitotic checkpoint component Mad1 causes chromosomal instability and resistance to microtubule poisons. Proc. Natl Acad. Sci. USA 109, E2205–E2214 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Klco, J. M. & Mullighan, C. G. Advances in germline predisposition to acute leukaemias and myeloid neoplasms. Nat. Rev. Cancer 21, 122–137 (2021).

    Article  CAS  PubMed  Google Scholar 

  189. Hazawa, M. et al. Disease-specific alteration of karyopherin-α subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma. Oncogene 39, 2212–2223 (2020).

    Article  CAS  PubMed  Google Scholar 

  190. Wang, M. et al. Prognostic significance of TRIM59 for cancer patient survival: A systematic review and meta-analysis. Medicine 98, e18024 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Aniththa, T. et al. Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and myelodysplastic syndrome. Haematologica 103, 614–625 (2018).

    Article  CAS  Google Scholar 

  192. Plo, I. et al. Genetic alterations of the thrombopoietin/MPL/JAK2 axis impacting megakaryopoiesis. Front. Endocrinol. 8, 234 (2017).

    Article  Google Scholar 

  193. Vainchenker, W. & Kralovics, R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood 129, 667–679 (2017).

    Article  CAS  PubMed  Google Scholar 

  194. Jakobsdottir, J. et al. Rare functional variant in TM2D3 is associated with late-onset Alzheimer’s disease. PLoS Genet. 12, e1006327 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Rick, J. W. et al. Fibronectin in malignancy: cancer-specific alterations, protumoral effects, and therapeutic implications. Semin. Oncol. 46, 284–290 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Watson, I. R., Irwin, M. S. & Ohh, M. NEDD8 pathways in cancer, sine quibus non. Cancer Cell 19, 168–176 (2011).

    Article  CAS  PubMed  Google Scholar 

  197. He, H. et al. A truncating germline mutation of TINF2 in individuals with thyroid cancer or melanoma results in longer telomeres. Thyroid 30, 204–213 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Rahman, S., Canny, M. D., Buschmann, T. A. & Latham, M. P. A survey of reported disease-related mutations in the MRE11-RAD50-NBS1 complex. Cells 9, 1678 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  199. Bolli, N. et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat. Commun. 5, 2997 (2014).

    Article  PubMed  CAS  Google Scholar 

  200. Huang, P. et al. Association of early-onset Alzheimer’s disease with germline-generated high affinity self-antigen load. Transl. Psychiatry 10, 146 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Wang, Z.-X. et al. Genetic association of HLA gene variants with MRI brain structure in Alzheimer’s disease. Mol. Neurobiol. 54, 3195–3204 (2017).

    Article  CAS  PubMed  Google Scholar 

  202. Steele, N. Z. R. et al. Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: a case–control study. PLoS Med. 14, e1002272 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Bykov, V. J. N., Eriksson, S. E., Bianchi, J. & Wiman, K. G. Targeting mutant p53 for efficient cancer therapy. Nat. Rev. Cancer 18, 89–102 (2018).

    Article  CAS  PubMed  Google Scholar 

  204. Singh, R., Letai, A. & Sarosiek, K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol. 20, 175–193 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Silva, A. G. et al. Germline BAX deletion in a patient with melanoma and gastrointestinal stromal tumor. Am. J. Gastroenterol. 108, 1372–1375 (2013).

    Article  CAS  PubMed  Google Scholar 

  206. Ionov, Y., Yamamoto, H., Krajewski, S., Reed, J. C. & Perucho, M. Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc. Natl Acad. Sci. USA 97, 10872–10877 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Han, Y. et al. DriverML: a machine learning algorithm for identifying driver genes in cancer sequencing studies. Nucleic Acids Res. 47, e45 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Wang, X. et al. Centromere protein U expression promotes non-small-cell lung cancer cell proliferation through FOXM1 and predicts poor survival. Cancer Manag. Res. 10, 6971–6984 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Ding, X., Duan, H. & Luo, H. Identification of core gene expression signature and key pathways in colorectal cancer. Front. Genet. 11, 45 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

A.J.S. received financial support from the Ann Melly Summer Scholarship in Oncology and from the US National Institutes of Health (NIH) under Ruth L. Kirschstein National Research Service Award F30DK127699 from the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and grant T32GM007347 from the US National Institute of General Medical Sciences (NIGMS). A.G.B. is supported by a Burroughs Wellcome Foundation career award for medical scientists and an NIH Director’s Early Independence Award from the National Institute of Health Common Fund (DP5 OD029586). M.R.S. is a Leukemia and Lymphoma Society Clinical Scholar and receives funding from the E.P. Evans Foundation, The Biff Ruttenberg Foundation, the Adventure Allie Fund, the Beverly and George Rawlings Directorship, and the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author information

Authors and Affiliations

  1. Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Alexander J. Silver, Alexander G. Bick & Michael R. Savona

  2. Division of Hematology and Oncology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA

    Alexander J. Silver & Michael R. Savona

  3. Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA

    Alexander G. Bick

  4. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    Alexander G. Bick & Michael R. Savona

  5. Center for Immunobiology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Alexander G. Bick & Michael R. Savona

Authors
  1. Alexander J. Silver
    View author publications

    Search author on:PubMed Google Scholar

  2. Alexander G. Bick
    View author publications

    Search author on:PubMed Google Scholar

  3. Michael R. Savona
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Each of the authors contributed to all aspects of the manuscript.

Corresponding author

Correspondence to Michael R. Savona.

Ethics declarations

Competing interests

A.J.S. and A.G.B. declare no competing interests. M.R.S. receives research funding from ALX Oncology, Astex, Incyte, Takeda and TG Therapeutics; has equity with Karyopharm; and serves as an advisor or consultant to AbbVie, Astex, BMS, Geron, Incyte, Karyopharm, Ryvu, Sierra Oncology, Takeda, Taiho and TG Therapeutics.

Additional information

Peer review information

Nature Reviews Genetics thanks G. Vassiliou and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Haematopoietic stem cells

(HSCs). Cells that are responsible for the creation of all blood cells in the human body and are multipotent in that they may differentiate into any type of mature blood cell. They are found in the bone marrow in adult humans.

Somatic

Variation in the genome arising from changes happening over the lifespan of an organism.

Clonal haematopoiesis

(CH). The presence of many blood cells originating from a single mutant stem or progenitor cell.

Germline

Variation in the genome arising from DNA that is passed from the parent to the offspring.

Mosaic loss of the Y chromosome

(mLOY). A common type of clonal haematopoiesis affecting XY individuals which is associated with the complete absence of the Y chromosome in the clonal cell population.

Mosaic chromosomal alterations

(mCAs). A type of clonal haematopoiesis in which a portion of the genome has been duplicated (copy number gain), lost (copy number loss) or replaced with DNA from another allele (copy-neutral loss of heterozygosity).

CH with unknown drivers

This is CH in which there is no evidence of a genetic mutation that is known to cause clonal expansion. In such cases, clonality may be ascertained by the presence of a unique pattern of somatic mutations throughout the genome that is only present in a subset of cells.

CH of indeterminate potential

(CHIP). A clinical term for a type of clonal haematopoiesis defined by single-nucleotide variants or small insertions/deletions (indels) in genes associated with myeloid malignancies in the presence of normal blood counts and at ≥2% variant allele fraction.

Variant allele fraction

(VAF). The percentage of measured DNA alleles that contain a specified variant. For example, if half of a population of diploid cells each harboured a single copy of JAK2V617F, the variant allele fraction for this mutation would be 25%.

Acute myeloid leukaemia

(AML). A blood cancer characterized by improper maturation of the myeloid lineage (monocytes and granulocytes), resulting in the production of many dysfunctional immature cells called blasts.

HSC transplantation

(HSCT). The provision of donor HSCs to patients with various types of malignant and non-malignant conditions. Autologous or allogeneic donor HSCs are provided to recipients after conditioning regimens of radiation and/or chemotherapy.

Allogeneic HSCT

HSCT involving the transplantation of histocompatible HSCs from a non-self donor to a recipient.

Autologous HSCT

HSCT involving the harvest of patient HSCs to be provided later as a ‘stem cell rescue’ after high-dose chemotherapy.

Myeloproliferative neoplasms

(MPNs). Haematological malignancies generally defined by the overproduction of myeloid cells, red blood cells or platelets.

Myelodysplastic syndromes

(MDS). A set of haematological malignancies with abnormal appearing cells within the bone marrow and reduced production of mature blood cells without increased levels of immature blasts.

Haematopoietic stem and progenitor cells

(HSPCs). A population of blood cells that includes multipotent HSCs but also more differentiated progenitor cells that are capable of producing many daughter cells but only within restricted lineages.

cis

mCAs in cis refers to an mCA lesion that affects the portion of the genome containing the risk allele.

trans

mCAs in trans refers to an mCA lesion affecting a different part of the genome than the DNA on which the risk allele is located.

DNA methylation

The presence of methyl groups added to the DNA base, often occurring on cytosine adjacent to a guanine (CpG). The methylation of DNA in gene promoter sequences may reduce gene expression.

Accelerated epigenetic ageing

Contrary to an individual’s chronological age defined by the passage of time, an individual’s epigenetic age is a measure of how the pattern of DNA methylation compares to the average pattern observed in the population across all ages. Accelerated epigenetic age means one’s DNA methylation pattern is more similar to the average for individuals who are chronologically older than oneself.

Horizontal pleiotropy

In Mendelian randomization, when a genetic variant exerts its effects on a measured outcome through mechanisms separate from the pathway being studied.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Silver, A.J., Bick, A.G. & Savona, M.R. Germline risk of clonal haematopoiesis. Nat Rev Genet 22, 603–617 (2021). https://doi.org/10.1038/s41576-021-00356-6

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41576-021-00356-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer