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.

  • Perspective
  • Published:

Acute myeloid leukemia

Universal genetic testing for inherited susceptibility in children and adults with myelodysplastic syndrome and acute myeloid leukemia: are we there yet?

Leukemia volume 32, pages 1482–1492 (2018)Cite this article

Subjects

Abstract

Comprehensive genomic profiling of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cases have enabled the detection and differentiation of driver and subclonal mutations, informed risk prognostication, and defined targeted therapies. These insights into disease biology, and management have made multigene-acquired mutation testing a critical part of the diagnostic assessment of patients with sporadic MDS and AML. More recently, our understanding of the role of an increasing number of inherited genetic factors on MDS/AML risk and management has rapidly progressed. In recognition of the growing impact of this field, clinical guidelines and disease classification systems for both MDS and AML have recently incorporated familial MDS/AML predisposition syndromes into their diagnostic algorithms. In this perspective piece, we contemplate the advantages, disadvantages, and barriers that would need to be overcome to incorporate inherited MDS/AML genetic testing into the upfront molecular diagnostic work-up of every MDS/AML patient. For centers already performing panel-based tumor-only testing, including genes associated with familial forms of MDS/AML (e.g., RUNX1, CEBPA, GATA2, TP53), we advocate optimizing these tests to detect all types of germline variants in these genes and moving toward upfront paired tumor/germline testing to maximize detection and streamline patient care.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    Article  PubMed  CAS  Google Scholar 

  2. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 2016;374:2209–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130:722–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Welch JS, Petti AA, Miller CA, Fronick CC, O’Laughlin M, Fulton RS, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375:2023–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Lindsley RC, Saber W, Mar BG, Redd R, Wang T, Haagenson MD, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376:536–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Kadri S, Long BC, Mujacic I, Zhen CJ, Wurst MN, Sharma S, et al. Clinical validation of a next-generation sequencing genomic oncology panel via cross-platform benchmarking against established amplicon sequencing assays. J Mol Diagn. 2017;19:43–56.

    Article  PubMed  CAS  Google Scholar 

  9. Keel SB, Scott A, Sanchez-Bonilla M, Ho PA, Gulsuner S, Pritchard CC, et al. Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients. Haematologica. 2016;101:1343–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Mandelker D, Zhang L, Kemel Y, Stadler ZK, Joseph V, Zehir A, et al. Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing. JAMA. 2017;318:825–35.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375:443–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N, et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. 2015;27:658–70.

    Article  PubMed  CAS  Google Scholar 

  13. Lewinsohn M, Brown AL, Weinel LM, Phung C, Rafidi G, Lee MK, et al. Novel germline DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood. 2016;127:1017–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Wlodarski M, Hirabayashi S, Pastor V, Stary J, Hasle H, Masetti R, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016;127:1387–97.

    Article  PubMed  CAS  Google Scholar 

  15. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003;21:2397–406.

  16. Yushak ML, Han G, Bouberhan S, Epstein L, DiGiovanna MP, Mougalian SS, et al. Patient preferences regarding incidental genomic findings discovered during tumor profiling. Cancer. 2016;122:1588–97.

    Article  PubMed  Google Scholar 

  17. Kanagal-Shamanna R, Loghavi S, DiNardo CD, Medeiros LJ, Garcia-Manero G, Jabbour E, et al. Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation. Haematologica. 2017;102:1661–70.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Noris P, Perrotta S, Seri M, Pecci A, Gnan C, Loffredo G, et al. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood. 2011;117:6673–80.

    Article  PubMed  CAS  Google Scholar 

  19. Quentin S, Cuccuini W, Ceccaldi R, Nibourel O, Pondarre C, Pagès MP, et al. Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions. Blood. 2011;117:e161–70.

    Article  PubMed  CAS  Google Scholar 

  20. Cioc AM, Wagner JE, MacMillan ML, DeFor T, Hirsch B. Diagnosis of myelodysplastic syndrome among a cohort of 119 patients with fanconi anemia: morphologic and cytogenetic characteristics. Am J Clin Pathol. 2010;133:92–100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Tawana K, Wang J, Renneville A, Bödör C, Hills R, Loveday C, et al. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood. 2015;126:1214–23.

    Article  PubMed  CAS  Google Scholar 

  22. Xiao H, Shi J, Luo Y, Tan Y, He J, Xie W, et al. First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation. Blood. 2011;117:5257–60.

    Article  PubMed  CAS  Google Scholar 

  23. Berger G, van den Berg E, Sikkema-Raddatz B, Abbott KM, Sinke RJ, Bungener LB, et al. Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation. Leukemia. 2017;31:520–2.

    Article  PubMed  CAS  Google Scholar 

  24. Peffault de Latour R, Peters C, Gibson B, Strahm B, Lankester A, de Heredia CD, et al. Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes. Bone Marrow Transplant. 2015;50:1168–72.

    Article  PubMed  CAS  Google Scholar 

  25. Dickinson RE, Griffin H, Bigley V, Reynard LN, Hussain R, Haniffa M, et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood. 2011;118:2656–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123:809–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356:1317–26.

    Article  PubMed  CAS  Google Scholar 

  28. Metcalfe K, Lynch HT, Foulkes WD, Tung N, Kim-Sing C, Olopade OI, et al. Effect of oophorectomy on survival after breast cancer in BRCA1 and BRCA2 mutation carriers. JAMA Oncol. 2015;1:306–13.

    Article  PubMed  Google Scholar 

  29. Møller P, Seppälä TT, Bernstein I, Holinski-Feder E, Sala P, Gareth Evans D, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut. 2017. Jul 28. Epub ahead of print.

  30. Churpek JE, Marquez R, Neistadt B, Klaussen K, Lee MK, Churpek MM, et al. Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia. Cancer. 2016;122:304–11.

    Article  PubMed  CAS  Google Scholar 

  31. Schulz E, Valentin A, Ulz P, Beham-Schmid C, Lind K, Rupp V, et al. Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1, and TP53 in patients with therapy related myeloid neoplasms. J Med Genet. 2012;49:422–8.

    Article  PubMed  CAS  Google Scholar 

  32. Furutani E, Shimamura A. Germline genetic predisposition to hematologic malignancy. J Clin Oncol. 2017;35:1018–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Brown AL, Churpek JE, Malcovati L, Döhner H, Godley LA. Recognition of familial myeloid neoplasia in adults. Semin Hematol. 2017;54:60–8.

    Article  PubMed  Google Scholar 

  34. Zhang J, Nichols KE, Downing JR. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2016;374:1391.

    Article  PubMed  Google Scholar 

  35. Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015;6:10086.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Pabst T, Eyholzer M, Haefliger S, Schardt J, Mueller BU. Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. J Clin Oncol. 2008;26:5088–93.

    Article  PubMed  CAS  Google Scholar 

  37. Taskesen E, Bullinger L, Corbacioglu A, Sanders MA, Erpelinck CA, Wouters BJ, et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood. 2011;117:2469–75.

    Article  PubMed  CAS  Google Scholar 

  38. Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33:3660–7.

    Article  PubMed  CAS  Google Scholar 

  39. Owen C, Toze C, Koochin A, Forrest D, Smith C, Stevens J, et al. Five new pedigress with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood . 2008;112:4639–45.

    Article  PubMed  CAS  Google Scholar 

  40. Churpek JE, Godley LA. How I diagnose and manage individuals at risk for inherited myeloid malignancies. Blood . 2016;128:1800–13.

    Article  CAS  Google Scholar 

  41. Wilson DB, Link DC, Mason PJ, Bessler M. Inherited bone marrow failure syndromes in adolescents and young adults. Ann Med. 2014;46:353–63.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Muramatsu H, Okuno Y, Yoshida K, Shiraishi Y, Doisaki S, Narita A, et al. Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes. Genet Med. 2017;19:796–802.

    Article  PubMed  CAS  Google Scholar 

  43. Ghemlas I, Li H, Zlateska B, Klaassen R, Fernandez CV, Yanofsky RA, et al. Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes. J Med Genet. 2015;52:575–84.

    Article  PubMed  CAS  Google Scholar 

  44. Gross M, Hanenberg H, Lobitz S, Friedl R, Herterich S, Dietrich R, et al. Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction. Cytogenet Genome Res. 2002;98:126–35.

    Article  PubMed  CAS  Google Scholar 

  45. Narumi S, Amano N, Ishii T, Katsumata N, Muroya K, Adachi M, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 2016;48:792–7.

    Article  PubMed  CAS  Google Scholar 

  46. Nagamachi A, Matsui H, Asou H, Ozaki Y, Aki D, Kanai A, et al. Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. Cancer Cell. 2013;24:305–17.

    Article  PubMed  CAS  Google Scholar 

  47. Kim G, Ison G, McKee AE, Zhang H, Tang S, Gwise T, et al. FDA Approval Summary: Olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res. 2015;21:4257–61.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA

    Kiran Tawana, Michael W. Drazer & Jane E. Churpek

  2. Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA

    Jane E. Churpek

Authors
  1. Kiran Tawana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael W. Drazer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jane E. Churpek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jane E. Churpek.

Ethics declarations

Conflict of interest:

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tawana, K., Drazer, M.W. & Churpek, J.E. Universal genetic testing for inherited susceptibility in children and adults with myelodysplastic syndrome and acute myeloid leukemia: are we there yet?. Leukemia 32, 1482–1492 (2018). https://doi.org/10.1038/s41375-018-0051-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-018-0051-y

This article is cited by

Search

Advanced search

Quick links