Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia

Mary L. McMaster, Sonja I. Berndt, Jianqing Zhang, Susan L. Slager, Shengchao Alfred Li, Claire M. Vajdic, Karin E. Smedby, Huihuang Yan, Brenda M. Birmann, Elizabeth E. Brown, Alex Smith, Geffen Kleinstern, Mervin M. Fansler, Christine Mayr, Bin Zhu, Charles C. Chung, Ju Hyun Park, Laurie Burdette, Belynda D. Hicks, Amy HutchinsonLauren R. Teras, Hans Olov Adami, Paige M. Bracci, James McKay, Alain Monnereau, Brian K. Link, Roel C.H. Vermeulen, Stephen M. Ansell, Ann Maria, W. Ryan Diver, Mads Melbye, Akinyemi I. Ojesina, Peter Kraft, Paolo Boffetta, Jacqueline Clavel, Edward Giovannucci, Caroline M. Besson, Federico Canzian, Ruth C. Travis, Paolo Vineis, Elisabete Weiderpass, Rebecca Montalvan, Zhaoming Wang, Meredith Yeager, Nikolaus Becker, Yolanda Benavente, Paul Brennan, Lenka Foretova, Marc Maynadie, Alexandra Nieters, Silvia de Sanjose, Anthony Staines, Lucia Conde, Jacques Riby, Bengt Glimelius, Henrik Hjalgrim, Nisha Pradhan, Andrew L. Feldman, Anne J. Novak, Charles Lawrence, Bryan A. Bassig, Qing Lan, Tongzhang Zheng, Kari E. North, Lesley F. Tinker, Wendy Cozen, Richard K. Severson, Jonathan N. Hofmann, Yawei Zhang, Rebecca D. Jackson, Lindsay M. Morton, Mark P. Purdue, Nilanjan Chatterjee, Kenneth Offit, James R. Cerhan, Stephen J. Chanock, Nathaniel Rothman, Joseph Vijai, Lynn R. Goldin, Christine F. Skibola, Neil E. Caporaso

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40–31.03, P = 1.36 × 10−54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45–6.96, P = 8.75 × 10−19). Both risk alleles are observed at a low frequency among controls (~2–3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.

Original languageEnglish (US)
Article number4182
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

    Fingerprint

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

McMaster, M. L., Berndt, S. I., Zhang, J., Slager, S. L., Li, S. A., Vajdic, C. M., Smedby, K. E., Yan, H., Birmann, B. M., Brown, E. E., Smith, A., Kleinstern, G., Fansler, M. M., Mayr, C., Zhu, B., Chung, C. C., Park, J. H., Burdette, L., Hicks, B. D., ... Caporaso, N. E. (2018). Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia. Nature communications, 9(1), [4182]. https://doi.org/10.1038/s41467-018-06541-2