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Rare germline variants in ATM are associated with chronic lymphocytic leukemia

Leukemia volume 31, pages 2244–2247 (2017)Cite this article

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Chronic lymphocytic leukemia (CLL) is a highly heritable cancer, with a 7.5-fold increased risk in first-degree relatives.1 However, inherited predisposition to CLL remains largely unexplained by traditional linkage or genome-wide association studies. Here, we hypothesized that CLL heritability might arise from rare coding variants not analyzed in previous studies.

We compared rare germline variants (minor allele frequency <0.01) in coding regions of 516 samples from CLL patients of European descent to those found in 8920 ethnically matched, normal population controls. This represents the largest and most comprehensive search for risk alleles in CLL exomes to date. To maximize our power to detect significant associations, we combined data from multiple sequencing studies (see Supplementary Methods and Supplementary Tables S1 and S2 for cohort descriptions).

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Acknowledgements

We thank all patients and physicians for trial participation and sample donation. We thank Myriam Mendila, Nancy Valente, Stephan Zurfluh, Michael Wenger and Jamie Wingate for their support in the CLL8 trial conception and conduct. Grant support: JRB is a clinical scholar of the Leukemia and Lymphoma Society and is supported by the Leukemia and Lymphoma Society (TRP# 6289-13) and the American Cancer Society (RSG-13-002-01-CCE). JRB would also like to acknowledge the support of the Melton Family Fund for CLL Research, the Susan and Gary Rosenbach Fund for Lymphoma Research, and the Okonow Lipton Family Lymphoma Research Fund. CJW acknowledges support from the Blavatnik Family Foundation and NIH/NCI (1R01CA182461-02, 1R01CA184922-01 and 1U10CA180861-01). CJW is a scholar of the Leukemia and Lymphoma Society. SS and ET are supported by the Else Kröner-Fresenius-Stiftung (2010_Kolleg24, 2012_A146) and Deutsche Forschungsgemeinschaft (SFB 1074 projects B1, B2). Genetic analyses in CLL8 were supported by Roche.

Author contributions

Conception and design: GT, MRI, AK, GG and JRB; development of methodology: GT, MRI, SK, WP, D-AL, AT-W, AK, GG and JRB. Acquisition of data: GT, MRI, SK, WP, AK, D-AL, MH, SS, CJW, GG and JRB; data analysis and interpretation: GT, MRI, SK, WP, AK, ET, HTK, ER, JB, SR, KF, AK, GG and JRB. Writing, review and/or revision of the manuscript: GT, MRI, D-AL, ESL, GG and JRB; administrative, technical or material support: GT, MRI, SK, CC, SB, SMF, KH and SG; study supervision: GG and JRB.

Author information

Author notes

  1. G Tiao and M R Improgo: These authors contributed equally to this work.

  2. G Getz and J R Brown: These authors jointly supervised this work.

Authors and Affiliations

  1. Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    G Tiao, M R Improgo, S Kasar, W Poh, A Kamburov, D-A Landau, A Taylor-Weiner, C Cibulskis, S Bahl, E Rheinbay, S Gabriel, E S Lander, C J Wu, A Kiezun, G Getz & J R Brown

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    M R Improgo, S Kasar, W Poh, D-A Landau, S M Fernandes, K Hoang, C J Wu & J R Brown

  3. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    M R Improgo, S Kasar, W Poh, D-A Landau, C J Wu & J R Brown

  4. Department of Internal Medicine III, Ulm University, Ulm, Germany

    E Tausch & S Stilgenbauer

  5. Department of Computational Biology and Biostatistics, Dana-Farber Cancer Institute, Boston, MA, USA

    H T Kim

  6. Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne, Germany

    J Bahlo, S Robrecht, K Fischer & M Hallek

  7. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    G Getz

  8. Department of Pathology, Harvard Medical School, Boston, MA, USA

    G Getz

Authors
  1. G Tiao
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  2. M R Improgo
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  17. K Fischer
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  18. M Hallek
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  20. E S Lander
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  24. G Getz
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Corresponding authors

Correspondence to G Getz or J R Brown.

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Tiao, G., Improgo, M., Kasar, S. et al. Rare germline variants in ATM are associated with chronic lymphocytic leukemia. Leukemia 31, 2244–2247 (2017). https://doi.org/10.1038/leu.2017.201

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