Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis-Associated Mutations throughout Adult Life

American Journal of Human Genetics

Volumn 101, Issue 1, 2017, Pages 50-64

  Acuna Hidalgo, Rocio ^a   Sengul, Hilal ^a   Steehouwer, Marloes ^a   van de Vorst, Maartje ^b   Vermeulen, Sita H ^b   Kiemeney, Lambertus A L M ^b   Veltman, Joris A ^b,c   Gilissen, Christian ^b   Hoischen, Alexander ^a,b  

^a RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

^b RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

^c NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

age related clonal hematopoiesis; DNMT3A; mosaicism; smMIPs; somatic mutations; ultra sensitive sequencing

Indexed keywords

DNA; DNA METHYLTRANSFERASE 3A; JANUS KINASE 2; MOLECULAR PROBE;

ADULT; ADULTHOOD; AGED; AGING; ARTICLE; CELL CLONE; CELL EXPANSION; CELL MUTANT; CLONAL EVOLUTION; CLONAL HEMATOPOIESIS; CONTROLLED STUDY; FEMALE; GENE FREQUENCY; GENE LOCUS; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL; HIGH THROUGHPUT SEQUENCING; HUMAN; INDEL MUTATION; LEUKEMIA; MALE; MOSAICISM; POINT MUTATION; PREVALENCE; PRIORITY JOURNAL; SOMATIC MUTATION; DNA MUTATIONAL ANALYSIS; GENETICS; METABOLISM; MIDDLE AGED; MOLECULAR PROBE; MUTATION; NUCLEOTIDE SEQUENCE; OPEN READING FRAME; PROCEDURES; REPRODUCIBILITY; RESTRICTION MAPPING; YOUNG ADULT;

ADULT; AGED; BASE SEQUENCE; CLONE CELLS; DNA MUTATIONAL ANALYSIS; GENETIC LOCI; HEMATOPOIESIS; HUMANS; MIDDLE AGED; MOLECULAR PROBES; MUTATION; OPEN READING FRAMES; REPRODUCIBILITY OF RESULTS; RESTRICTION MAPPING; YOUNG ADULT;

EID: 85021356728     PISSN: 00029297     EISSN: 15376605     Source Type: Journal    
DOI: 10.1016/j.ajhg.2017.05.013     Document Type: Article

References (64)

1. Yadav, V.K., DeGregori, J., De, S., The landscape of somatic mutations in protein coding genes in apparently benign human tissues carries signatures of relaxed purifying selection. Nucleic Acids Res. 44 (2016), 2075–2084.
2. Genovese, G., Kähler, A.K., Handsaker, R.E., Lindberg, J., Rose, S.A., Bakhoum, S.F., Chambert, K., Mick, E., Neale, B.M., Fromer, M., et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371 (2014), 2477–2487.
3. Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P.V., Mar, B.G., Lindsley, R.C., Mermel, C.H., Burtt, N., Chavez, A., et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371 (2014), 2488–2498.
4. Xie, M., Lu, C., Wang, J., McLellan, M.D., Johnson, K.J., Wendl, M.C., McMichael, J.F., Schmidt, H.K., Yellapantula, V., Miller, C.A., et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20 (2014), 1472–1478.
5. McKerrell, T., Park, N., Moreno, T., Grove, C.S.S., Ponstingl, H., Stephens, J., Crawley, C., Craig, J., Scott, M.A.A., Hodkinson, C., et al., Understanding Society Scientific Group. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 10 (2015), 1239–1245.
6. 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, 2016, 12484.
7. Martincorena, I., Roshan, A., Gerstung, M., Ellis, P., Van Loo, P., McLaren, S., Wedge, D.C., Fullam, A., Alexandrov, L.B., Tubio, J.M., et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348 (2015), 880–886.
8. Abyzov, A., Mariani, J., Palejev, D., Zhang, Y., Haney, M.S., Tomasini, L., Ferrandino, A.F., Rosenberg Belmaker, L.A., Szekely, A., Wilson, M., et al. Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492 (2012), 438–442.
9. Gao, Z., Wyman, M.J., Sella, G., Przeworski, M., Interpreting the dependence of mutation rates on age and time. PLoS Biol., 14, 2016, e1002355.
10. Ramsey, M.J., Moore, D.H. 2nd, Briner, J.F., Lee, D.A., Olsen, La., Senft, J.R., Tucker, J.D., The effects of age and lifestyle factors on the accumulation of cytogenetic damage as measured by chromosome painting. Mutat. Res. 338 (1995), 95–106.
11. McKerrell, T., Vassiliou, G.S., Aging as a driver of leukemogenesis. Sci. Transl. Med., 7, 2015, 306fs38.
12. Stratton, M.R., Campbell, P.J., Futreal, P.A., The cancer genome. Nature 458 (2009), 719–724.
13. Adams, P.D., Jasper, H., Rudolph, K.L., Aging-induced stem cell mutations as drivers for disease and cancer. Cell Stem Cell 16 (2015), 601–612.
14. Chaudhury, S.S., Morison, J.K., Gibson, B.E.S., Keeshan, K., Insights into cell ontogeny, age, and acute myeloid leukemia. Exp. Hematol. 43 (2015), 745–755.
15. Corces-Zimmerman, M.R., Majeti, R., Pre-leukemic evolution of hematopoietic stem cells: the importance of early mutations in leukemogenesis. Leukemia 28 (2014), 2276–2282.
16. Steensma, D.P., Bejar, R., Jaiswal, S., Lindsley, R.C., Sekeres, M.A., Hasserjian, R.P., Ebert, B.L., Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126 (2015), 9–16.
17. Akunuru, S., Geiger, H., Aging, clonality, and rejuvenation of hematopoietic stem cells. Trends Mol. Med. 22 (2016), 701–712.
18. Beerman, I., Bhattacharya, D., Zandi, S., Sigvardsson, M., Weissman, I.L., Bryder, D., Rossi, D.J., Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc. Natl. Acad. Sci. USA 107 (2010), 5465–5470.
19. Geiger, H., de Haan, G., Florian, M.C., The ageing haematopoietic stem cell compartment. Nat. Rev. Immunol. 13 (2013), 376–389.
20. Rozhok, A.I., DeGregori, J., Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations. Proc. Natl. Acad. Sci. USA 112 (2015), 8914–8921.
21. Holstege, H., Pfeiffer, W., Sie, D., Hulsman, M., Nicholas, T.J., Lee, C.C., Ross, T., Lin, J., Miller, M.A., Ylstra, B., et al. Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis. Genome Res. 24 (2014), 733–742.
22. Shlush, L.I., Zandi, S., Itzkovitz, S., Schuh, A.C., Aging, clonal hematopoiesis and preleukemia: not just bad luck?. Int. J. Hematol. 102 (2015), 513–522.
23. Hiatt, J.B., Pritchard, C.C., Salipante, S.J., O'Roak, B.J., Shendure, J., Single molecule molecular inversion probes for targeted, high-accuracy detection of low-frequency variation. Genome Res. 23 (2013), 843–854.
24. Neveling, K., Mensenkamp, A.R., Derks, R., Kwint, M., Ouchene, H., Steehouwer, M., van Lier, B., Bosgoed, E., Rikken, A., Tychon, M., et al. BRCA testing by single-molecule molecular inversion probes. Clin. Chem. 63 (2017), 503–512.
25. Eijkelenboom, A., Kamping, E.J., Kastner-van Raaij, A.W., Hendriks-Cornelissen, S.J., Neveling, K., Kuiper, R.P., Hoischen, A., Nelen, M.R., Ligtenberg, M.J.L., Tops, B.B.J., Reliable next-generation sequencing of formalin-fixed, paraffin-embedded tissue using single molecule tags. J. Mol. Diagn. 18 (2016), 851–863.
26. Weren, R.D.A., Mensenkamp, A.R., Simons, M., Eijkelenboom, A., Sie, A.S., Ouchene, H., van Asseldonk, M., Gomez-Garcia, E.B., Blok, M.J., de Hullu, J.A., et al. Novel BRCA1 and BRCA2 tumor test as basis for treatment decisions and referral for genetic counselling of patients with ovarian carcinomas. Hum. Mutat. 38 (2017), 226–235.
27. Carlston, C.M., O'Donnell-Luria, A.H., Underhill, H.R., Cummings, B.B., Weisburd, B., Minikel, E.V., Birnbaum, D.P., Tvrdik, T., MacArthur, D.G., Mao, R., Exome Aggregation Consortium. Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz syndrome. Hum. Mutat. 38 (2017), 517–523.
28. Goriely, A., Wilkie, A.O.M., Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am. J. Hum. Genet. 90 (2012), 175–200.
29. Maher, G.J., McGowan, S.J., Giannoulatou, E., Verrill, C., Goriely, A., Wilkie, A.O.M., Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes. Proc. Natl. Acad. Sci. USA 113 (2016), 2454–2459.
30. Yoon, S.-R., Choi, S.-K., Eboreime, J., Gelb, B.D., Calabrese, P., Arnheim, N., Age-dependent germline mosaicism of the most common noonan syndrome mutation shows the signature of germline selection. Am. J. Hum. Genet. 92 (2013), 917–926.
31. Giannoulatou, E., McVean, G., Taylor, I.B., McGowan, S.J., Maher, G.J., Iqbal, Z., Pfeifer, S.P., Turner, I., Burkitt Wright, E.M.M., Shorto, J., et al. Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline. Proc. Natl. Acad. Sci. USA 110 (2013), 20152–20157.
32. Goriely, A., Hansen, R.M.S., Taylor, I.B., Olesen, I.A., Jacobsen, G.K., McGowan, S.J., Pfeifer, S.P., McVean, G.A.T., Rajpert-De Meyts, E., Wilkie, A.O.M., Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat. Genet. 41 (2009), 1247–1252.
33. Galesloot, T.E., Vermeulen, S.H., Swinkels, D.W., de Vegt, F., Franke, B., den Heijer, M., de Graaf, J., Verbeek, A.L., Kiemeney, L.A., Cohort Profile: The Nijmegen Biomedical Study (NBS). Int. J. Epidemiol., 2017, dyw268.
34. Champion, K.J., Bunag, C., Estep, A.L., Jones, J.R., Bolt, C.H., Rogers, R.C., Rauen, K.A., Everman, D.B., Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. Clin. Genet. 79 (2011), 468–474.
35. Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cavé, H., Verloes, A., Okamoto, N., Hennekam, R.C.M., Gillessen-Kaesbach, G., Wieczorek, D., et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat. Genet. 38 (2006), 294–296.
36. Tartaglia, M., Martinelli, S., Stella, L., Bocchinfuso, G., Flex, E., Cordeddu, V., Zampino, G., Burgt, Iv., Palleschi, A., Petrucci, T.C., et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am. J. Hum. Genet. 78 (2006), 279–290.
37. Groesser, L., Herschberger, E., Ruetten, A., Ruivenkamp, C., Lopriore, E., Zutt, M., Langmann, T., Singer, S., Klingseisen, L., Schneider-Brachert, W., et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat. Genet. 44 (2012), 783–787.
38. Hoischen, A., Krumm, N., Eichler, E.E., Prioritization of neurodevelopmental disease genes by discovery of new mutations. Nat. Neurosci. 17 (2014), 764–772.
39. Lelieveld, S.H., Reijnders, M.R.F., Pfundt, R., Yntema, H.G., Kamsteeg, E.J., de Vries, P., de Vries, B.B.A., Willemsen, M.H., Kleefstra, T., Löhner, K., et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat. Neurosci. 19 (2016), 1194–1196.
40. McRae, J.F., Clayton, S., Fitzgerald, T.W., Kaplanis, J., Prigmore, E., Rajan, D., Sifrim, A., Aitken, S., Akawi, N., Alvi, M., et al. Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation. bioRxiv, 2016, 10.1101/049056.
41. Boyle, E.A., O'Roak, B.J., Martin, B.K., Kumar, A., Shendure, J., MIPgen: optimized modeling and design of molecular inversion probes for targeted resequencing. Bioinformatics 30 (2014), 2670–2672.
42. O'Roak, B.J., Vives, L., Fu, W., Egertson, J.D., Stanaway, I.B., Phelps, I.G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338 (2012), 1619–1622.
43. Mancini, M., Hasan, S.K., Ottone, T., Lavorgna, S., Ciardi, C., Angelini, D.F., Agostini, F., Venditti, A., Lo-Coco, F., Two novel methods for rapid detection and quantification of DNMT3A R882 mutations in acute myeloid leukemia. J. Mol. Diagn. 17 (2015), 179–184.
44. Wright, C.F., Fitzgerald, T.W., Jones, W.D., Clayton, S., McRae, J.F., van Kogelenberg, M., King, D.A., Ambridge, K., Barrett, D.M., Bayzetinova, T., et al., DDD study. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet 385 (2015), 1305–1314.
45. Goriely, A., McVean, G.A.T., Röjmyr, M., Ingemarsson, B., Wilkie, A.O.M., Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science 301 (2003), 643–646.
46. Choi, S.-K., Yoon, S.-R., Calabrese, P., Arnheim, N., Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B. PLoS Genet., 8, 2012, e1002420.
47. Greenman, C., Stephens, P., Smith, R., Dalgliesh, G.L., Hunter, C., Bignell, G., Davies, H., Teague, J., Butler, A., Stevens, C., et al. Patterns of somatic mutation in human cancer genomes. Nature 446 (2007), 153–158.
48. Goodwin, S., McPherson, J.D., McCombie, W.R., Coming of age: ten years of next-generation sequencing technologies. Nat. Rev. Genet. 17 (2016), 333–351.
49. Chen, L., Liu, P., Evans, T.C. Jr., Ettwiller, L.M., DNA damage is a pervasive cause of sequencing errors, directly confounding variant identification. Science 355 (2017), 752–756.
50. Wong, T.N., Ramsingh, G., Young, A.L., Miller, C.A., Touma, W., Welch, J.S., Lamprecht, T.L., Shen, D., Hundal, J., Fulton, R.S., et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 518 (2015), 552–555.
51. Takahashi, K., Wang, F., Kantarjian, H., Doss, D., Khanna, K., Thompson, E., Zhao, L., Patel, K., Neelapu, S., Gumbs, C., et al. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol. 18 (2017), 100–111.
52. Alexandrov, L.B., Jones, P.H., Wedge, D.C., Sale, J.E., Campbell, P.J., Nik-Zainal, S., Stratton, M.R., Clock-like mutational processes in human somatic cells. Nat. Genet. 47 (2015), 1402–1407.
53. Moehrle, B.M., Geiger, H., Aging of hematopoietic stem cells: DNA damage and mutations?. Exp. Hematol. 44 (2016), 895–901.
54. Mason, C.C., Khorashad, J.S., Tantravahi, S.K., Kelley, T.W., Zabriskie, M.S., Yan, D., Pomicter, A.D., Reynolds, K.R., Eiring, A.M., Kronenberg, Z., et al. Age-related mutations and chronic myelomonocytic leukemia. Leukemia 30 (2016), 906–913.
55. Tefferi, A., Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 24 (2010), 1128–1138.
56. Link, D.C., Walter, M.J., 'CHIP'ping away at clonal hematopoiesis. Leukemia 30 (2016), 1633–1635.
57. Grimwade, D., Ivey, A., Huntly, B.J.P., Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood 127 (2016), 29–41.
58. Forbes, S.A., Beare, D., Gunasekaran, P., Leung, K., Bindal, N., Boutselakis, H., Ding, M., Bamford, S., Cole, C., Ward, S., et al. COSMIC: exploring the world's knowledge of somatic mutations in human cancer. Nucleic Acids Res. 43 (2015), D805–D811.
59. Yang, L., Rau, R., Goodell, M.A., DNMT3A in haematological malignancies. Nat. Rev. Cancer 15 (2015), 152–165.
60. Hoischen, A., van Bon, B.W.M., Rodríguez-Santiago, B., Gilissen, C., Vissers, L.E.L.M., de Vries, P., Janssen, I., van Lier, B., Hastings, R., Smithson, S.F., et al. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat. Genet. 43 (2011), 729–731.
61. Kosaki, R., Terashima, H., Kubota, M., Kosaki, K., Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation. Am. J. Med. Genet. A. 173 (2017), 250–253.
62. Martinelli, S., De Luca, A., Stellacci, E., Rossi, C., Checquolo, S., Lepri, F., Caputo, V., Silvano, M., Buscherini, F., Consoli, F., et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am. J. Hum. Genet. 87 (2010), 250–257.
63. Niemeyer, C.M., Kang, M.W., Shin, D.H., Furlan, I., Erlacher, M., Bunin, N.J., Bunda, S., Finklestein, J.Z., Sakamoto, K.M., Gorr, T.A., et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat. Genet. 42 (2010), 794–800.
64. Chen, R., Shi, L., Hakenberg, J., Naughton, B., Sklar, P., Zhang, J., Zhou, H., Tian, L., Prakash, O., Lemire, M., et al. Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases. Nat. Biotechnol. 34 (2016), 531–538.