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Acute myeloid leukemia

Rare germline variant contributions to myeloid malignancy susceptibility

Leukemia volume 34, pages 1675–1678 (2020)Cite this article

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Although the somatic landscapes of myeloid malignancies have been extensively characterized, germline contributions to the disease are not well understood. The limited number of germline variants that have been implicated in myeloid malignancy susceptibility are mostly rare and have largely been identified in families [1, 2]. Newfound predisposition alleles are also likely to be rare, given the dearth of published common susceptibility alleles and the nature of known susceptibility variants.

To investigate the roles of rare variants in myeloid malignancy susceptibility, we analyzed whole-exome sequence data from the germlines of 690 patients (Supplementary Tables 1–3; Supplementary Figs. 1A and 2). We assessed the presence and impact of rare variants in genes with previously implicated susceptibility alleles, as well as in genes with known or putative roles in myeloid neoplasms or cancer in general. This focused our analysis on 657 genes (Supplementary Table 4). After applying a stringent variant-calling and annotation pipeline (Supplementary Figs. 3 and 4), rare variants were defined as those with population allele frequencies below 1% that alter protein composition (missense/nonsense substitutions, in-frame/frameshift indels, and splice site variants) (Supplementary Fig. 1B, C; Supplementary Table 5).

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Fig. 1: Myeloperoxidase (MPO) as a candidate susceptibility gene in myeloid malignancy.
Fig. 2: Autosomal recessive genes and Fanconi anemia genes have higher overall and truncating rare germline variant burden.

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Acknowledgements

The authors with to acknowledge the individuals and families that were part of the study presented here, as well as researchers who made the exomes and metadata available to us. This study makes use of data generated by the Cancer Genomics Project at the University of Tokyo, the International Cancer Genome Consortium, the St. Jude Children’s Research Hospital Genomes for Kids Study, St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project, the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative managed by the NCI, The Cancer Genome Atlas. This work was supported in part by American Cancer Society grant 123436-RSG-12–159–01-DMC (TL), US National Institute of Health (NIH) grant R35 HL135795 (JPM), the Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain (PI/17/0575), 2017 SGR288 (GRC) Generalitat de Catalunya, and CERCA Program/Generalitat de Catalunya, Fundació Internacional Josep Carreras and from Celgene International (FS). The research leading to this work has received funding from “la Caixa” Foundation (FS). This work made use of the High Performance Computing Resource in the Core Facility for Advanced Research Computing at Case Western Reserve University.

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Authors and Affiliations

  1. Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA

    Samuel T. Li, Janet Wang, Ruipeng Wei, Ruqi Shi & Thomas LaFramboise

  2. Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Vera Adema, Yasunobu Nagata, Cassandra M. Kerr, Teodora Kuzmanovic, Bartlomiej Przychodzen & Jaroslaw P. Maciejewski

  3. Myelodysplastic Syndrome Research Group, Josep Carreras Leukaemia Research Institute, Institut Català d’Oncologia-Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain

    Francesc Sole

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  1. Samuel T. Li
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Li, S.T., Wang, J., Wei, R. et al. Rare germline variant contributions to myeloid malignancy susceptibility. Leukemia 34, 1675–1678 (2020). https://doi.org/10.1038/s41375-019-0701-8

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