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Juvenile myelomonocytic leukemia due to a germline CBL Y371C mutation: 35-year follow-up of a large family

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Abstract

Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative neoplasm that arises from malignant transformation of the stem cell compartment and results in increased production of myeloid cells. Somatic and germline variants in CBL (Casitas B-lineage lymphoma proto-oncogene) have been associated with JMML. We report an incompletely penetrant CBL Y371C mutation discovered by whole-exome sequencing in three individuals with JMML in a large pedigree with 35 years of follow-up. The Y371 residue is highly evolutionarily conserved among CBL orthologs and paralogs. In silico bioinformatics prediction programs suggested that the Y371C mutation is highly deleterious. Protein structural modeling revealed that the Y371C mutation abrogated the ability of the CBL protein to adopt a conformation that is required for ubiquitination. Clinically, the three mutation-positive JMML individuals exhibited variable clinical courses; in two out of three, primary hematologic abnormalities persisted into adulthood with minimal clinical symptoms. The penetrance of the CBL Y371C mutation was 30 % for JMML and 40 % for all leukemia. Of the 8 mutation carriers in the family with available photographs, only one had significant dysmorphic features; we found no evidence of a clinical phenotype consistent with a “CBL syndrome”. Although CBL Y371C has been previously reported in familial JMML, we are the first group to follow a complete pedigree harboring this mutation for an extended period, revealing additional information about this variant’s penetrance, function and natural history.

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Acknowledgments

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.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Authors and Affiliations

  1. Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive Rm 6E450, Bethesda, MD, 20892, USA

    Anand Pathak, Alexander Pemov, Ramita Dewan, Mark H. Greene & Douglas R. Stewart

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

    Mary L. McMaster, Neil Caporaso & Lynn R. Goldin

  3. Advanced Biomedical Computing Center, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Sarangan Ravichandran

  4. Cytogenetic and Microscopy Core, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Evgenia Pak & Amalia Dutra

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

    Hyo Jung Lee, Aurelie Vogt, Xijun Zhang & Meredith Yeager

  6. Flow Cytometry Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Stacie Anderson & Martha Kirby

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  1. Anand Pathak
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  2. Alexander Pemov
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  3. Mary L. McMaster
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  7. Amalia Dutra
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  8. Hyo Jung Lee
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NCI DCEG Cancer Genomics Research Laboratory

NCI DCEG Cancer Sequencing Working Group

Corresponding authors

Correspondence to Anand Pathak or Douglas R. Stewart.

Additional information

The members of NCI DCEG Cancer Genomics Research Laboratory and NCI DCEG Cancer Sequencing Working Group are listed in “Appendix”.

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Appendix

Appendix

NCI DCEG Cancer Genomics Research Laboratory: Sara Bass, Joseph Boland, Laurie Burdette, Salma Chowdhury, Michael Cullen, Casey Dagnall, Herbert Higson, Amy A. Hutchinson, Kristine Jones, Sally Larson, Kerrie Lashley, Hyo Jung Lee, Wen Luo, Michael Malasky, Michelle Manning, Jason Mitchell, David Roberson, Aurelie Vogt, Mingyi Wang, Meredith Yeager, Xijun Zhang.

NCI DCEG Cancer Sequencing Working Group: Bari Ballew, Stephen J. Chanock, Alisa M. Goldstein, Allan Hildesheim, Nan Hu, Maria Teresa Landi, Jennifer Loud, Phuong L. Mai, Lisa Mirabello, Lindsay Morton, Dilys Parry, Melissa Rotunno, Sharon A. Savage, Philip R. Taylor, Geoffrey S. Tobias, Margaret A. Tucker, Jeannette Wong, Xiaohong R. Yang, Guoqin Yu.

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Pathak, A., Pemov, A., McMaster, M.L. et al. Juvenile myelomonocytic leukemia due to a germline CBL Y371C mutation: 35-year follow-up of a large family. Hum Genet 134, 775–787 (2015). https://doi.org/10.1007/s00439-015-1550-9

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