Skip to main content

Thank you for visiting 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.

Myelodysplastic syndrome

Targeted gene panels identify a high frequency of pathogenic germline variants in patients diagnosed with a hematological malignancy and at least one other independent cancer



The majority of studies assessing the contribution of pathogenic germline variants (PGVs) to cancer predisposition have focused on patients with single cancers. We analyzed 45 known cancer predisposition genes (CPGs) in germline samples of 202 patients with hematological malignancies (HMs) plus one or more other independent cancer managed at major tertiary medical centers on two different continents. This included 120 patients with therapy-related myeloid neoplasms (t-MNs), where the HM occurred after cytotoxic treatment for a first malignancy, and 82 patients with multiple cancers in which the HM was not preceded by cytotoxic therapy (MC-HM). Using American College of Medical Genetics/Association for Molecular Pathology variant classification guidelines, 13% of patients had PGVs, most frequently identified in CHEK2 (17% of PGVs), BRCA1 (13%), DDX41 (13%), and TP53 (7%). The frequency of PGVs in MC-HM was higher than in t-MN, although not statistically significant (18 vs. 9%; p = 0.085). The frequency of PGVs in lymphoid and myeloid HM patients was similar (19 vs. 17.5%; p > 0.9). Critically, patients with PGVs in BRCA1, BRCA2 or TP53 did not satisfy current clinical phenotypic criteria for germline testing. Our data suggest that a personal history of multiple cancers, one being a HM, should trigger screening for PGVs.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Distribution of pathogenic germline variants (PGVs) in patients with t-MN and MC-HM.
Fig. 2: Frequency of PGV is higher in patients with ≥ 2 cancers.


  1. 1.

    Rahman N. Realizing the promise of cancer predisposition genes. Nature. 2014;505:302–8.

    CAS  Article  Google Scholar 

  2. 2.

    Peffault de Latour R, Soulier J. How I treat MDS and AML in Fanconi anemia. Blood. 2016;127:2971–9.

    CAS  Article  Google Scholar 

  3. 3.

    Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. NCCN clinial practice guidelines in Oncology: National Comprehensive Cancer Network; 2020;18.

  4. 4.

    Huang KL, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, et al. Pathogenic germline variants in 10,389 adult cancers. Cell. 2018;173:355–70.

    CAS  Article  Google Scholar 

  5. 5.

    Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373:2336–46.

    CAS  Article  Google Scholar 

  6. 6.

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

    CAS  Article  Google Scholar 

  7. 7.

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

    CAS  Article  Google Scholar 

  8. 8.

    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 Gen. 2012;49:422–8.

    CAS  Article  Google Scholar 

  9. 9.

    Martin MG, Jacoby M, Shao J, Deych E, Graubert T, Walter MJ. BRCA1 and BRCA2 nucleotide variants in young women with therapy related acute myeloid leukemia. Blood. 2009;114:1102.

    Article  Google Scholar 

  10. 10.

    Voso MT, Fabiani E, Zang Z, Fianchi L, Falconi G, Padella A, et al. Fanconi anemia gene variants in therapy-related myeloid neoplasms. Blood Cancer J. 2015;5:e323.

    CAS  Article  Google Scholar 

  11. 11.

    Guidugli L, Johnson AK, Alkorta-Aranburu G, Nelakuditi V, Arndt K, Churpek JE, et al. Clinical utility of gene panel-based testing for hereditary myelodysplastic syndrome/acute leukemia predisposition syndromes. Leukemia. 2017;31:1226–9.

    CAS  Article  Google Scholar 

  12. 12.

    Singhal D, Wee LYA, Kutyna MM, Chhetri R, Geoghegan J, Schreiber AW, et al. The mutational burden of therapy-related myeloid neoplasms is similar to primary myelodysplastic syndrome but has a distinctive distribution. Leukemia. 2019;33:2842–53.

    CAS  Article  Google Scholar 

  13. 13.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–23.

    Article  Google Scholar 

  14. 14.

    Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, et al. Revisiting li-fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015;33:2345–52.

    CAS  Article  Google Scholar 

  15. 15.

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

    CAS  Article  Google Scholar 

  16. 16.

    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.

    CAS  Article  Google Scholar 

  17. 17.

    Brown AL, Hahn CN, Scott HS. Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA). Blood. 2020;136:24–35.

    CAS  Article  Google Scholar 

  18. 18.

    Feurstein S, Churpek JE, Walsh T, Keel S, Hakkarainen M, Schroeder T, et al. Germline variants drive myelodysplastic syndrome in young adults. Leukemia. 2021.

  19. 19.

    Sébert M, Passet M, Raimbault A, Rahmé R, Raffoux E, Sicre de Fontbrune F, et al. Germline DDX41 mutations define a significant entity within adult MDS/AML patients. Blood. 2019;134:1441–4.

    Article  Google Scholar 

  20. 20.

    Galera P, Hsu AP, Wang W, Droll S, Chen R, Schwartz JR, et al. Donor-derived MDS/AML in families with germline GATA2 mutation. Blood. 2018;132:1994–8.

    CAS  Article  Google Scholar 

  21. 21.

    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.

    CAS  Article  Google Scholar 

  22. 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.

    CAS  Article  Google Scholar 

  23. 23.

    Dietz AC, Orchard PJ, Baker KS, Giller RH, Savage SA, Alter BP, et al. Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita. Bone Marrow Transpl. 2011;46:98–104.

    CAS  Article  Google Scholar 

  24. 24.

    Ebens CL, MacMillan ML, Wagner JE. Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations. Expert Rev Hematol. 2017;10:81–97.

    CAS  Article  Google Scholar 

  25. 25.

    Abou Tayoun AN, Pesaran T, DiStefano MT, Oza A, Rehm HL, Biesecker LG, et al. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum Mutat. 2018;39:1517–24.

    Article  Google Scholar 

  26. 26.

    Brnich SE, Abou Tayoun AN, Couch FJ, Cutting GR, Greenblatt MS, Heinen CD, et al. Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework. Genome Med. 2019;12:3.

    Article  Google Scholar 

  27. 27.

    Ruijs MW, Verhoef S, Rookus MA, Pruntel R, van der Hout AH, Hogervorst FB, et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet. 2010;47:421–8.

    CAS  Article  Google Scholar 

  28. 28.

    Chompret A, Abel A, Stoppa-Lyonnet D, Brugieres L, Pages S, Feunteun J, et al. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet. 2001;38:43–7.

    CAS  Article  Google Scholar 

  29. 29.

    Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, et al. 2009 Version of the Chompret Criteria for Li Fraumeni Syndrome. J Clin Oncol. 2009;27:e108–9.

    Article  Google Scholar 

  30. 30.

    Varley JM, Thorncroft M, McGown G, Appleby J, Kelsey AM, Tricker KJ, et al. A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li–Fraumeni patients carrying a mutation to the TP53 gene. Oncogene. 1997;14:865–71.

    CAS  Article  Google Scholar 

  31. 31.

    Srivastava S, Tong YA, Devadas K, Zou ZQ, Sykes VW, Chen Y, et al. Detection of both mutant and wild-type p53 protein in normal skin fibroblasts and demonstration of a shared ‘second hit’ on p53 in diverse tumors from a cancer-prone family with Li-Fraumeni syndrome. Oncogene. 1992;7:987–91.

    CAS  PubMed  Google Scholar 

  32. 32.

    Metzger AK, Sheffield VC, Duyk G, Daneshvar L, Edwards MS, Cogen PH. Identification of a germ-line mutation in the p53 gene in a patient with an intracranial ependymoma. Proc Natl Acad Sci USA. 1991;88:7825–9.

    CAS  Article  Google Scholar 

  33. 33.

    Daly MB, Pilarski R, Berry M, Buys SS, Farmer M, Friedman S, et al. NCCN guidelines insights: genetic/familial high-risk assessment: breast and ovarian, version 2.2017. J Natl Compr Canc Netw. 2016;15:9–20.

    Article  Google Scholar 

  34. 34.

    Gupta S, Provenzale D, Llor X, Halverson AL, Grady W, Chung DC, et al. NCCN guidelines insights: genetic/familial high-risk assessment: colorectal, version 2.2019. J Natl Compr Canc Netw. 2019;17:1032–41.

    Article  Google Scholar 

  35. 35.

    Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002;70:1555–63.

    CAS  Article  Google Scholar 

Download references


We thank the research subjects and their families for their continued engagement into research in the germline genetic contribution to hematopoietic malignancies.


DS- Royal Adelaide Hospital (RAH) Research Committee, AR Clarkson Scholarship, MyIP 8414. DKH- Health Services Charitable Gifts Board, Sail for Cancer Project Grant, MyIP 10118; RAH Research Committee, Clinical Project Grant, MyIP 10960; NHMRC Medical Research Future Fund (MRFF), Investigator Grant, MRF1195517. CNH, ALB, HSS- National Health and Medical Research Council, Project Grants APP1024215, APP1164601. LG-The Cancer Research Foundation.

Author information




DS: Variant annotation, analyzed data and wrote the manuscript. CNH: Variant annotation, analyzed data and edited the manuscript. LYAW: Processed samples, variant annotation, analyzed data and edited the manuscript. SF and LM: Variant annotation, analyzed data and edited the manuscript. MMK: Processed samples, cultured mesenchymal stromal samples, and edited the manuscript. RC: Provided clinical details and edited the manuscript. LE, AWS, JF, PP-SW, and SG: Analyzed bioinformatics data and provided critical comments. MB, WTP, SM and SD: Analyzed data and provided critical comments. David T and SP: Provided scientific input and edited the manuscript. ALB, RD, NP, and DT: Provided critical comments and edited the manuscript. HSS: Provided scientific input and edited the manuscript. LG: Helped in developing the project, contributed data and edited the manuscript. DKH: Developed and supervised the project, analyzed data and wrote the manuscript.

Corresponding authors

Correspondence to Lucy A. Godley or Devendra K. Hiwase.

Ethics declarations

Conflict of interest

LAG receives royalties from UptoDate, Inc. for a co-authored article on inherited predisposition to hematopoietic malignancies. HSS—received honoraria from Celgene.

Additional information

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Singhal, D., Hahn, C.N., Feurstein, S. et al. Targeted gene panels identify a high frequency of pathogenic germline variants in patients diagnosed with a hematological malignancy and at least one other independent cancer. Leukemia (2021).

Download citation


Quick links