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 D 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 & 61 others Lauren R. Teras, Hans Olov Adami, Paige M. Bracci, James McKay, Alain Monnereau, Brian K. Link, Roel C.H. Vermeulen, Stephen Maxted 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

1 Citation (Scopus)

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

Waldenstrom Macroglobulinemia
loci
magnetic permeability
Lymphoma
Alleles
frequency control
genome
Genome-Wide Association Study
B-Cell Lymphoma
Transcription
Genetic Predisposition to Disease
Computer Simulation
Genes
Cells
Cell Proliferation
low frequencies
cells
Neoplasms

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., ... 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

Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia. / McMaster, Mary L.; Berndt, Sonja I.; Zhang, Jianqing; Slager, Susan L; Li, Shengchao Alfred; Vajdic, Claire M.; Smedby, Karin E.; Yan, Huihuang D; Birmann, Brenda M.; Brown, Elizabeth E.; Smith, Alex; Kleinstern, Geffen; Fansler, Mervin M.; Mayr, Christine; Zhu, Bin; Chung, Charles C.; Park, Ju Hyun; Burdette, Laurie; Hicks, Belynda D.; Hutchinson, Amy; Teras, Lauren R.; Adami, Hans Olov; Bracci, Paige M.; McKay, James; Monnereau, Alain; Link, Brian K.; Vermeulen, Roel C.H.; Ansell, Stephen Maxted; Maria, Ann; Diver, W. Ryan; Melbye, Mads; Ojesina, Akinyemi I.; Kraft, Peter; Boffetta, Paolo; Clavel, Jacqueline; Giovannucci, Edward; Besson, Caroline M.; Canzian, Federico; Travis, Ruth C.; Vineis, Paolo; Weiderpass, Elisabete; Montalvan, Rebecca; Wang, Zhaoming; Yeager, Meredith; Becker, Nikolaus; Benavente, Yolanda; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; Nieters, Alexandra; de Sanjose, Silvia; Staines, Anthony; Conde, Lucia; Riby, Jacques; Glimelius, Bengt; Hjalgrim, Henrik; Pradhan, Nisha; Feldman, Andrew L; Novak, Anne J; Lawrence, Charles; Bassig, Bryan A.; Lan, Qing; Zheng, Tongzhang; North, Kari E.; Tinker, Lesley F.; Cozen, Wendy; Severson, Richard K.; Hofmann, Jonathan N.; Zhang, Yawei; Jackson, Rebecca D.; Morton, Lindsay M.; Purdue, Mark P.; Chatterjee, Nilanjan; Offit, Kenneth; Cerhan, James R; Chanock, Stephen J.; Rothman, Nathaniel; Vijai, Joseph; Goldin, Lynn R.; Skibola, Christine F.; Caporaso, Neil E.

In: Nature Communications, Vol. 9, No. 1, 4182, 01.12.2018.

Research output: Contribution to journalArticle

McMaster, ML, Berndt, SI, Zhang, J, Slager, SL, Li, SA, Vajdic, CM, Smedby, KE, Yan, HD, 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
McMaster, Mary L. ; Berndt, Sonja I. ; Zhang, Jianqing ; Slager, Susan L ; Li, Shengchao Alfred ; Vajdic, Claire M. ; Smedby, Karin E. ; Yan, Huihuang D ; Birmann, Brenda M. ; Brown, Elizabeth E. ; Smith, Alex ; Kleinstern, Geffen ; Fansler, Mervin M. ; Mayr, Christine ; Zhu, Bin ; Chung, Charles C. ; Park, Ju Hyun ; Burdette, Laurie ; Hicks, Belynda D. ; Hutchinson, Amy ; Teras, Lauren R. ; Adami, Hans Olov ; Bracci, Paige M. ; McKay, James ; Monnereau, Alain ; Link, Brian K. ; Vermeulen, Roel C.H. ; Ansell, Stephen Maxted ; Maria, Ann ; Diver, W. Ryan ; Melbye, Mads ; Ojesina, Akinyemi I. ; Kraft, Peter ; Boffetta, Paolo ; Clavel, Jacqueline ; Giovannucci, Edward ; Besson, Caroline M. ; Canzian, Federico ; Travis, Ruth C. ; Vineis, Paolo ; Weiderpass, Elisabete ; Montalvan, Rebecca ; Wang, Zhaoming ; Yeager, Meredith ; Becker, Nikolaus ; Benavente, Yolanda ; Brennan, Paul ; Foretova, Lenka ; Maynadie, Marc ; Nieters, Alexandra ; de Sanjose, Silvia ; Staines, Anthony ; Conde, Lucia ; Riby, Jacques ; Glimelius, Bengt ; Hjalgrim, Henrik ; Pradhan, Nisha ; Feldman, Andrew L ; Novak, Anne J ; Lawrence, Charles ; Bassig, Bryan A. ; Lan, Qing ; Zheng, Tongzhang ; North, Kari E. ; Tinker, Lesley F. ; Cozen, Wendy ; Severson, Richard K. ; Hofmann, Jonathan N. ; Zhang, Yawei ; Jackson, Rebecca D. ; Morton, Lindsay M. ; Purdue, Mark P. ; Chatterjee, Nilanjan ; Offit, Kenneth ; Cerhan, James R ; Chanock, Stephen J. ; Rothman, Nathaniel ; Vijai, Joseph ; Goldin, Lynn R. ; Skibola, Christine F. ; Caporaso, Neil E. / Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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.",
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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 D

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 Maxted

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.

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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.

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