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

TitleTwo high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenstrom macroglobulinemia
Publication TypeJournal Article
Year of Publication2018
AuthorsMcMaster, ML, Berndt, SI, Zhang, J, Slager, SL, Li, SA, Vajdic, CM, Smedby, KE, Yan, H, Birmann, BM, Brown, EE, Smith, A, Kleinstern, G, Fansler, MM, Mayr, C, Zhu, B, Chung, CC, Park, JH, Burdette, L, Hicks, BD, Hutchinson, A, Teras, LR, Adami, HO, Bracci, PM, McKay, J, Monnereau, A, Link, BK, Vermeulen, RCH, Ansell, SM, Maria, A, Diver, WR, Melbye, M, Ojesina, AI, Kraft, P, Boffetta, P, Clavel, J, Giovannucci, E, Besson, CM, Canzian, F, Travis, RC, Vineis, P, Weiderpass, E, Montalvan, R, Wang, Z, Yeager, M, Becker, N, Benavente, Y, Brennan, P, Foretova, L, Maynadie, M, Nieters, A, de Sanjose, S, Staines, A, Conde, L, Riby, J, Glimelius, B, Hjalgrim, H, Pradhan, N, Feldman, AL, Novak, AJ, Lawrence, C, Bassig, BA, Lan, Q, Zheng, T, North, KE, Tinker, LF, Cozen, W, Severson, RK, Hofmann, JN, Zhang, Y, Jackson, RD, Morton, LM, Purdue, MP, Chatterjee, N, Offit, K, Cerhan, JR, Chanock, SJ, Rothman, N, Vijai, J, Goldin, LR, Skibola, CF, Caporaso, NE
JournalNat Commun
Volume9
Pagination4182
Date PublishedOct 10
ISBN Number2041-1723
Accession Number30305637
Abstract

Waldenstrom 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 x 10(-54)) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45-6.96, P = 8.75 x 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.

PMCID

PMC6180091