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Epidemiology

In search of genetic factors predisposing to familial hairy cell leukemia (HCL): exome-sequencing of four multiplex HCL pedigrees

Leukemia volume 34, pages 1934–1938 (2020)Cite this article

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Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder named for its characteristic hair-like cytoplasmic projections from the malignant cells. HCL is classified as an indolent lymphoproliferative neoplasm, representing ~2% of all leukemias with ~1240 new cases diagnosed annually in the US; median age-at-onset is 55 years [1]. It affects males more than females (4:1), and whites more than African-Americans [1]. Although familial and sporadic HCL exhibit similar clinical features, no characteristic germline genetic variation has been found. Familial HCL is rare with fewer than 20 families reported in the literature. Thirteen of the 15 reported pedigrees had two affected individuals; the remaining two pedigrees harbored three, including the family reported here [2,3,4,5]. Investigators have speculated that HCL may be an HLA-linked disorder but, in aggregate, the data are inconclusive [3,4,5]. The discovery that a somatic BRAF mutation (V600E) was nearly universal in HCL (but absent in other B-cell neoplasms) provided major insight into disease biology, identifying a critical therapeutic target [6], but no germline genetic susceptibility variants have been identified. In this study we applied high-throughput sequencing technology to four multiplex HCL pedigrees, seeking to identify shared germline variants conferring HCL susceptibility. In addition, we used CRISPR/Cas9-based genome editing to introduce CASP9 p.H237P, one of the variants shared by all four affected members of the largest pedigree, into a model cell line, followed by measurements of cellular caspase-9 activity and apoptotic response.

To gain insight into whether genes with deleterious variants segregating within each family belonged to similar ontological categories or cellular pathways, we compared each of the four gene lists to pre-defined gene-sets in Gene Ontology Biological Process, Kyoto Encyclopedia of Genes and Genomes, Reactome and WikiPathways databases and identified functional categories shared by the pedigrees’ gene lists (Supplementary Table S2). Neutrophil-mediated immunity (ATP8B4, PNP, SLC44A2, and RAB37) and signaling by G-protein coupled receptor (MC3R, FZD6, NMUR2, KSR2, RGS9, and GPR35) were the most frequently shared ontological categories and pathways (3/4 pedigrees). Other pathways (shared by 2/4 families) included MAPK and RAS signaling (IGF2, KSR2, and CACNA1A), apoptosis (CASP9, IGF2), PI3K-Akt Signaling (CASP9, IGF2), response to DNA damage (CASP9, INTS3), and signaling by EGFR/ERBB4/FGFR/PDGF/SCF-KIT (CASP9, KSR2) (Supplementary Table S2).

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Fig. 1: Pedigree diagrams of four multiplex HCL families.
Fig. 2: Caspase-9 and caspase-3/7 activities in staurosporine-treated CRISPR-unedited HCT116 cells and in HCT116 cells carrying caspase-9 p.H237P and p.R192C substitutions.

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Acknowledgements

This project was supported by the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Rockville, MD. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. This work utilized the computational resources of the NIH High Performance Computing Biowulf cluster. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The Vancouver Lymphoid Cancer Families Study is supported by the Canadian Institutes for Health Research, MOP-130311, and the BC Cancer Foundation. The Vancouver NHL case-control study was supported by the Canadian Cancer Society through the National Cancer Institute of Canada, and the Canadian Institutes of Health Research. The authors thank Joseph M. Connors, MD for his help in initiating the Vancouver Lymphoid Cancer Families Study and referral of one of the families with two affected individuals. The authors would like to thank Katharine Beebe, MPH, Westat, Inc., Rockville, MD, for her help with Fig. 1 preparation.

NCI DCEG Cancer Genomics Research Laboratory

Belynda D. Hicks14, Amy H. Hutchinson14, Michelle Manning14, Aurelie Vogt14, Kristine Jones14, Russell Williams14, Kedest Teshome14, Herb Higson14, Joseph Boland14, Sara Bass14, Bin Zhu14, Wen Luo14, Mingyi Wang14, Dongjing Wu14

Author information

Author notes

  1. These authors contributed equally: Alexander Pemov, Anand Pathak

Authors and Affiliations

  1. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Alexander Pemov, Anand Pathak, Ramita Dewan, Jessica Merberg, Sirisha Karra, Jung Kim, Mark H. Greene, Mary L. McMaster & Douglas R. Stewart

  2. Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada

    Samantha J. Jones & Angela Brooks-Wilson

  3. Medical Genetics, University of British Columbia, Vancouver, BC, Canada

    Samantha J. Jones

  4. Laboratory of Molecular Biology, Clinical Immunotherapy Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Evgeny Arons & Robert J. Kreitman

  5. Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA

    Sarangan Ravichandran & Brian T. Luke

  6. Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA

    Shalabh Suman & Meredith Yeager

  7. The Ernest and Helen Scott Hematological Research Institute, University of Leicester, Leicester, UK

    Martin J. S. Dyer

  8. Department of Preventive Medicine, Creighton University, Omaha, NE, USA

    Henry T. Lynch

  9. Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Neil E. Caporaso

  10. Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Lynn R. Goldin

  11. Population Oncology, BC Cancer, Vancouver, BC, Canada

    John J. Spinelli

  12. School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada

    John J. Spinelli

  13. Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada

    Angela Brooks-Wilson

  14. NCI DCEG Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, USA

    Belynda D. Hicks, Michelle Manning, Aurelie Vogt, Kristine Jones, Russell Williams, Kedest Teshome, Herb Higson, Joseph Boland, Sara Bass,  Bin Zhu, Wen Luo, Mingyi Wang & Dongjing Wu

Author notes

  1. Members of the NCI DCEG Cancer Genomics Research Laboratory are listed below Acknowledgements.

    • Deceased: Henry T. Lynch

      • Henry T. Lynch
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    NCI DCEG Cancer Genomics Research Laboratory

    • Belynda D. Hicks
    • , Amy H. Hutchinson
    • , Michelle Manning
    • , Aurelie Vogt
    • , Kristine Jones
    • , Russell Williams
    • , Kedest Teshome
    • , Herb Higson
    • , Joseph Boland
    • , Sara Bass
    • ,  Bin Zhu
    • , Wen Luo
    • , Mingyi Wang
    •  & Dongjing Wu

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    Correspondence to Douglas R. Stewart.

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    Members of the NCI DCEG Cancer Genomics Research Laboratory are listed below Acknowledgements.

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    Pemov, A., Pathak, A., Jones, S.J. et al. In search of genetic factors predisposing to familial hairy cell leukemia (HCL): exome-sequencing of four multiplex HCL pedigrees. Leukemia 34, 1934–1938 (2020). https://doi.org/10.1038/s41375-019-0702-7

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