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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

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Abstract

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.

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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.

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Acknowledgements

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

Funding

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.

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Contributions

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.

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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.

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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). https://doi.org/10.1038/s41375-021-01246-w

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