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 Hutchinson; Lauren 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

doi:10.1038/s41467-018-06541-2

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 journal › Article › peer-review

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 language	English
Article number	4182
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06541-2
State	Published - 1 Dec 2018
Externally published	Yes

Bibliographical note

Funding Information:
We wish to thank Seth A. Brodie, PhD, for his critical reading of the manuscript and his intellectual contributions to the functional experimental approach. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 03/07/2018. 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. Further acknowledgements are provided in Supplementary Note 1.

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

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

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10.1038/s41467-018-06541-2

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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), Article 4182. https://doi.org/10.1038/s41467-018-06541-2

@article{866d7313a1e646e88eb9e0ae9802651f,

title = "Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenstr{\"o}m macroglobulinemia",

abstract = "Waldenstr{\"o}m 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.",

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

note = "Funding Information: We wish to thank Seth A. Brodie, PhD, for his critical reading of the manuscript and his intellectual contributions to the functional experimental approach. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 03/07/2018. 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. Further acknowledgements are provided in Supplementary Note 1. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-06541-2",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

McMaster, 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 2018, 'Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia', Nature Communications, vol. 9, no. 1, 4182. https://doi.org/10.1038/s41467-018-06541-2

TY - JOUR

T1 - Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia

AU - McMaster, Mary L.

AU - Berndt, Sonja I.

AU - Zhang, Jianqing

AU - Slager, Susan L.

AU - Li, Shengchao Alfred

AU - Vajdic, Claire M.

AU - Smedby, Karin E.

AU - Yan, Huihuang

AU - Birmann, Brenda M.

AU - Brown, Elizabeth E.

AU - Smith, Alex

AU - Kleinstern, Geffen

AU - Fansler, Mervin M.

AU - Mayr, Christine

AU - Zhu, Bin

AU - Chung, Charles C.

AU - Park, Ju Hyun

AU - Burdette, Laurie

AU - Hicks, Belynda D.

AU - Hutchinson, Amy

AU - Teras, Lauren R.

AU - Adami, Hans Olov

AU - Bracci, Paige M.

AU - McKay, James

AU - Monnereau, Alain

AU - Link, Brian K.

AU - Vermeulen, Roel C.H.

AU - Ansell, Stephen M.

AU - Maria, Ann

AU - Diver, W. Ryan

AU - Melbye, Mads

AU - Ojesina, Akinyemi I.

AU - Kraft, Peter

AU - Boffetta, Paolo

AU - Clavel, Jacqueline

AU - Giovannucci, Edward

AU - Besson, Caroline M.

AU - Canzian, Federico

AU - Travis, Ruth C.

AU - Vineis, Paolo

AU - Weiderpass, Elisabete

AU - Montalvan, Rebecca

AU - Wang, Zhaoming

AU - Yeager, Meredith

AU - Becker, Nikolaus

AU - Benavente, Yolanda

AU - Brennan, Paul

AU - Foretova, Lenka

AU - Maynadie, Marc

AU - Nieters, Alexandra

AU - de Sanjose, Silvia

AU - Staines, Anthony

AU - Conde, Lucia

AU - Riby, Jacques

AU - Glimelius, Bengt

AU - Hjalgrim, Henrik

AU - Pradhan, Nisha

AU - Feldman, Andrew L.

AU - Novak, Anne J.

AU - Lawrence, Charles

AU - Bassig, Bryan A.

AU - Lan, Qing

AU - Zheng, Tongzhang

AU - North, Kari E.

AU - Tinker, Lesley F.

AU - Cozen, Wendy

AU - Severson, Richard K.

AU - Hofmann, Jonathan N.

AU - Zhang, Yawei

AU - Jackson, Rebecca D.

AU - Morton, Lindsay M.

AU - Purdue, Mark P.

AU - Chatterjee, Nilanjan

AU - Offit, Kenneth

AU - Cerhan, James R.

AU - Chanock, Stephen J.

AU - Rothman, Nathaniel

AU - Vijai, Joseph

AU - Goldin, Lynn R.

AU - Skibola, Christine F.

AU - Caporaso, Neil E.

N1 - Funding Information: We wish to thank Seth A. Brodie, PhD, for his critical reading of the manuscript and his intellectual contributions to the functional experimental approach. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 03/07/2018. 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. Further acknowledgements are provided in Supplementary Note 1. Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85054606609&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-06541-2

DO - 10.1038/s41467-018-06541-2

M3 - Article

C2 - 30305637

AN - SCOPUS:85054606609

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4182

ER -

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

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Bibliographical note

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