A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci

Kristin A. Rand; Chi Song; Eric Dean; Daniel J. Serie; Karen Curtin; Xin Sheng; Donglei Hu; Carol Ann Huff; Leon Bernal-Mizrachi; H. Michael Tomasson; Sikander Ailawadhi; Seema Singhal; Karen Pawlish; Edward S. Peters; Cathryn H. Bock; Alex Stram; David J. Van Den Berg; Christopher K. Edlund; David V. Conti; Todd Zimmerman; Amie E. Hwang; Scott Huntsman; John Graff; Ajay Nooka; Yinfei Kong; Silvana L. Pregja; Sonja I. Berndt; William J. Blot; John Carpten; Graham Casey; Lisa Chu; W. Ryan Diver; Victoria L. Stevens; Michael R. Lieber; Phyllis J. Goodman; Anselm J.M. Hennis; Ann W. Hsing; Jayesh Mehta; Rick A. Kittles; Suzanne Kolb; Eric A. Klein; Cristina Leske; Adam B. Murphy; Barbara Nemesure; Christine Neslund-Dudas; Sara S. Strom; Ravi Vij; Benjamin A. Rybicki; Janet L. Stanford; Lisa B. Signorello; John S. Witte; Christine B. Ambrosone; Parveen Bhatti; Esther M. John; Leslie Bernstein; Wei Zheng; Andrew F. Olshan; Jennifer J. Hu; Regina G. Ziegler; Sarah J. Nyante; Elisa V. Bandera; Brenda M. Birmann; Sue A. Ingles; Michael F. Press; Djordje Atanackovic; Martha J. Glenn; Lisa A. Cannon-Albright; Brandt Jones; Guido Tricot; Thomas G. Martin; Shaji K. Kumar; Jeffrey L. Wolf; Sandra L. Deming Halverson; Nathaniel Rothman; Angela R. Brooks-Wilson; S. Vincent Rajkumar; Laurence N. Kolonel; Stephen J. Chanock; Susan L. Slager; Richard K. Severson; Nalini Janakiraman; Howard R. Terebelo; Elizabeth E. Brown; Anneclaire J. De Roos; Ann F. Mohrbacher; Graham A. Colditz; Graham G. Giles; John J. Spinelli; Brian C. Chiu; Nikhil C. Munshi; Kenneth C. Anderson; Joan Levy; Jeffrey A. Zonder; Robert Z. Orlowski; Sagar Lonial; Nicola J. Camp; Celine M. Vachon; Elad Ziv; Daniel O. Stram; Dennis J. Hazelett; Christopher A. Haiman; Wendy Cozen

doi:10.1158/1055-9965.EPI-15-1193

A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci

Kristin A. Rand, Chi Song, Eric Dean, Daniel J. Serie, Karen Curtin, Xin Sheng, Donglei Hu, Carol Ann Huff, Leon Bernal-Mizrachi, H. Michael Tomasson, Sikander Ailawadhi, Seema Singhal, Karen Pawlish, Edward S. Peters, Cathryn H. Bock, Alex Stram, David J. Van Den Berg, Christopher K. Edlund, David V. Conti, Todd ZimmermanAmie E. Hwang, Scott Huntsman, John Graff, Ajay Nooka, Yinfei Kong, Silvana L. Pregja, Sonja I. Berndt, William J. Blot, John Carpten, Graham Casey, Lisa Chu, W. Ryan Diver, Victoria L. Stevens, Michael R. Lieber, Phyllis J. Goodman, Anselm J.M. Hennis, Ann W. Hsing, Jayesh Mehta, Rick A. Kittles, Suzanne Kolb, Eric A. Klein, Cristina Leske, Adam B. Murphy, Barbara Nemesure, Christine Neslund-Dudas, Sara S. Strom, Ravi Vij, Benjamin A. Rybicki, Janet L. Stanford, Lisa B. Signorello, John S. Witte, Christine B. Ambrosone, Parveen Bhatti, Esther M. John, Leslie Bernstein, Wei Zheng, Andrew F. Olshan, Jennifer J. Hu, Regina G. Ziegler, Sarah J. Nyante, Elisa V. Bandera, Brenda M. Birmann, Sue A. Ingles, Michael F. Press, Djordje Atanackovic, Martha J. Glenn, Lisa A. Cannon-Albright, Brandt Jones, Guido Tricot, Thomas G. Martin, Shaji K. Kumar, Jeffrey L. Wolf, Sandra L. Deming Halverson, Nathaniel Rothman, Angela R. Brooks-Wilson, S. Vincent Rajkumar, Laurence N. Kolonel, Stephen J. Chanock, Susan L. Slager, Richard K. Severson, Nalini Janakiraman, Howard R. Terebelo, Elizabeth E. Brown, Anneclaire J. De Roos, Ann F. Mohrbacher, Graham A. Colditz, Graham G. Giles, John J. Spinelli, Brian C. Chiu, Nikhil C. Munshi, Kenneth C. Anderson, Joan Levy, Jeffrey A. Zonder, Robert Z. Orlowski, Sagar Lonial, Nicola J. Camp, Celine M. Vachon, Elad Ziv, Daniel O. Stram, Dennis J. Hazelett, Christopher A. Haiman, Wendy Cozen

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry- European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 30 end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10^-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-kB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional.

Original language	English
Pages (from-to)	1609-1618
Number of pages	10
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	25
Issue number	12
DOIs	https://doi.org/10.1158/1055-9965.EPI-15-1193
State	Published - Dec 1 2016

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10.1158/1055-9965.EPI-15-1193

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Rand, K. A., Song, C., Dean, E., Serie, D. J., Curtin, K., Sheng, X., Hu, D., Huff, C. A., Bernal-Mizrachi, L., Tomasson, H. M., Ailawadhi, S., Singhal, S., Pawlish, K., Peters, E. S., Bock, C. H., Stram, A., Van Den Berg, D. J., Edlund, C. K., Conti, D. V., ... Cozen, W. (2016). A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci. Cancer Epidemiology Biomarkers and Prevention, 25(12), 1609-1618. https://doi.org/10.1158/1055-9965.EPI-15-1193

@article{8824c1f474454274b3dd2e218261c726,

title = "A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci",

abstract = "Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry- European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 30 end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-kB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional.",

author = "Rand, {Kristin A.} and Chi Song and Eric Dean and Serie, {Daniel J.} and Karen Curtin and Xin Sheng and Donglei Hu and Huff, {Carol Ann} and Leon Bernal-Mizrachi and Tomasson, {H. Michael} and Sikander Ailawadhi and Seema Singhal and Karen Pawlish and Peters, {Edward S.} and Bock, {Cathryn H.} and Alex Stram and {Van Den Berg}, {David J.} and Edlund, {Christopher K.} and Conti, {David V.} and Todd Zimmerman and Hwang, {Amie E.} and Scott Huntsman and John Graff and Ajay Nooka and Yinfei Kong and Pregja, {Silvana L.} and Berndt, {Sonja I.} and Blot, {William J.} and John Carpten and Graham Casey and Lisa Chu and Diver, {W. Ryan} and Stevens, {Victoria L.} and Lieber, {Michael R.} and Goodman, {Phyllis J.} and Hennis, {Anselm J.M.} and Hsing, {Ann W.} and Jayesh Mehta and Kittles, {Rick A.} and Suzanne Kolb and Klein, {Eric A.} and Cristina Leske and Murphy, {Adam B.} and Barbara Nemesure and Christine Neslund-Dudas and Strom, {Sara S.} and Ravi Vij and Rybicki, {Benjamin A.} and Stanford, {Janet L.} and Signorello, {Lisa B.} and Witte, {John S.} and Ambrosone, {Christine B.} and Parveen Bhatti and John, {Esther M.} and Leslie Bernstein and Wei Zheng and Olshan, {Andrew F.} and Hu, {Jennifer J.} and Ziegler, {Regina G.} and Nyante, {Sarah J.} and Bandera, {Elisa V.} and Birmann, {Brenda M.} and Ingles, {Sue A.} and Press, {Michael F.} and Djordje Atanackovic and Glenn, {Martha J.} and Cannon-Albright, {Lisa A.} and Brandt Jones and Guido Tricot and Martin, {Thomas G.} and Kumar, {Shaji K.} and Wolf, {Jeffrey L.} and {Deming Halverson}, {Sandra L.} and Nathaniel Rothman and Brooks-Wilson, {Angela R.} and Rajkumar, {S. Vincent} and Kolonel, {Laurence N.} and Chanock, {Stephen J.} and Slager, {Susan L.} and Severson, {Richard K.} and Nalini Janakiraman and Terebelo, {Howard R.} and Brown, {Elizabeth E.} and {De Roos}, {Anneclaire J.} and Mohrbacher, {Ann F.} and Colditz, {Graham A.} and Giles, {Graham G.} and Spinelli, {John J.} and Chiu, {Brian C.} and Munshi, {Nikhil C.} and Anderson, {Kenneth C.} and Joan Levy and Zonder, {Jeffrey A.} and Orlowski, {Robert Z.} and Sagar Lonial and Camp, {Nicola J.} and Vachon, {Celine M.} and Elad Ziv and Stram, {Daniel O.} and Hazelett, {Dennis J.} and Haiman, {Christopher A.} and Wendy Cozen",

note = "Funding Information: This study was supported by the National Cancer Institute at the NIH (1R01CA134786 to W. Cozen and Christopher A. Haiman; 2P50CA100707 to K.C. Anderson; Myeloma SPORE 2P50CA100707 Project 6 to K.C. Anderson, W. Cozen, and D.V. Conti; R01CA152336 and R01CA134674 to N.J. Camp; P50 CA142509 and R01CA184464 to R.Z. Orlowski; R21CA155951, R25CA76023, R01CA186646, U54CA118948 Project 3 and P30CA13148 (seed grant) to E.E. Brown; and R21CA191896 and K24CA169004 to E. Ziv). The study also received support from the Leukemia Lymphoma Society (LLS 6067-090) to N.J. Camp, the American Cancer Society (IRG60-001-47) to E.E. Brown, and the Steve and Nancy Grand Multiple Myeloma Translational Initiative to E. Ziv. Data collection from the cancer registries was supported by the National Cancer Institute Surveillance Epidemiology and End Results Population-based Registry Program, NIH, Department of Health and Human Services, under contracts N01-PC-35139 (to USC for Los Angeles County), HHSN 261201300021I, N01PC-2013- 00021 (to the New Jersey State Cancer Registry), and HHSN261201000026C (to the Utah Cancer Registry). Additional support for collection of incident multiple myeloma patient data was obtained from the Utah State Department of Health and the University of Utah, the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR), the National Program of Cancer Registries of the Centers for Disease Control and Prevention (5U58DP003931-02 to the New Jersey State Cancer Registry and 1U58DP000807-01 to the California Cancer Registry), the Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant, P30 CA42014 and by the USC Norris Comprehensive Cancer Center Core grant P30CA014089 from the National Cancer Institute. The collection of patients used in this publication was supported in part by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. AAPC studies: The MEC is supported by NIH grants CA63464, CA54281, CA1326792, CA148085, and HG004726. Genotyping of the PLCO samples was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH. LAAPC was funded by grant 99-00524V- 10258 from the Cancer Research Fund, under Interagency Agreement #97- 12013 (University of California contract #98-00924V) with the Department of Health Services Cancer Research Program. Cancer incidence data for the MEC and LAAPC studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with Federal funds from the NCI, NIH, Department of Health andHumanServices, under Contract No. N01- PC-35139, and the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant number 1U58DP000807-3 from the Centers for Disease Control and Prevention. KCPCS was supported by NIH grants CA056678, CA082664, and CA092579, with additional support from the Fred Hutchinson Cancer Research Center and the Intramural Program of the NationalHumanGenome Research Institute.MDAwas supported by grants, CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388. CaP Genes was supported by CA88164 and CA127298. SELECT was funded in part by Public Health Service grants U10 CA37429 (C.D. Blanke) and UM1 CA182883 (I.M. Thompson/C.M. Tangen) from the National Cancer Institute. GECAP was supported by NIH grant ES011126. SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt-Ingram Cancer Center (CA68485). AABC studies: AABC was supported by a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to CAH (W81XWH-08-1-0383), the Norris Foundation, P01-CA151135 and U19-CA148065. Each of the participating studies was supported by the following grants: MEC (NIH grants R01-CA63464, R37-CA54281 and UM1-CA164973); CARE (National Institute for Child Health and Development grant NO1-HD-3-3175, K05 CA136967); WCHS [U.S. Army Medical Research and Material Command (USAMRMC) grant DAMD-17-01-0-0334, the NIH grant R01-CA100598, and the Breast Cancer Research Foundation]; SFBCS (NIH grant R01-CA77305 and United States Army Medical Research Program grant DAMD17-96-6071); NC-BCFR (NIH grant U01-CA69417); CBCS (NIH Specialized Program of Research Excellence in Breast Cancer, grant number P50-CA58223, and Center for Environmental Health and Susceptibility National Institute of Environmental Health Sciences, NIH, grant number P30-ES10126); PLCO (Intramural Research Program, National Cancer Institute, NIH); NBHS (National Institutes of Health grant R01-CA100374); WFBC (NIH grant R01-CA73629). The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, NIH under RFA-CA-06-503 and through cooperative agreements withmembers of the Breast Cancer Family Registry and Principal Investigators. Publisher Copyright: {\textcopyright} 2016 AACR.",

year = "2016",

month = dec,

day = "1",

doi = "10.1158/1055-9965.EPI-15-1193",

language = "English",

volume = "25",

pages = "1609--1618",

journal = "Cancer Epidemiology Biomarkers and Prevention",

issn = "1055-9965",

number = "12",

}

Rand, KA, Song, C, Dean, E, Serie, DJ, Curtin, K, Sheng, X, Hu, D, Huff, CA, Bernal-Mizrachi, L, Tomasson, HM, Ailawadhi, S, Singhal, S, Pawlish, K, Peters, ES, Bock, CH, Stram, A, Van Den Berg, DJ, Edlund, CK, Conti, DV, Zimmerman, T, Hwang, AE, Huntsman, S, Graff, J, Nooka, A, Kong, Y, Pregja, SL, Berndt, SI, Blot, WJ, Carpten, J, Casey, G, Chu, L, Diver, WR, Stevens, VL, Lieber, MR, Goodman, PJ, Hennis, AJM, Hsing, AW, Mehta, J, Kittles, RA, Kolb, S, Klein, EA, Leske, C, Murphy, AB, Nemesure, B, Neslund-Dudas, C, Strom, SS, Vij, R, Rybicki, BA, Stanford, JL, Signorello, LB, Witte, JS, Ambrosone, CB, Bhatti, P, John, EM, Bernstein, L, Zheng, W, Olshan, AF, Hu, JJ, Ziegler, RG, Nyante, SJ, Bandera, EV, Birmann, BM, Ingles, SA, Press, MF, Atanackovic, D, Glenn, MJ, Cannon-Albright, LA, Jones, B, Tricot, G, Martin, TG, Kumar, SK, Wolf, JL, Deming Halverson, SL, Rothman, N, Brooks-Wilson, AR, Rajkumar, SV, Kolonel, LN, Chanock, SJ, Slager, SL, Severson, RK, Janakiraman, N, Terebelo, HR, Brown, EE, De Roos, AJ, Mohrbacher, AF, Colditz, GA, Giles, GG, Spinelli, JJ, Chiu, BC, Munshi, NC, Anderson, KC, Levy, J, Zonder, JA, Orlowski, RZ, Lonial, S, Camp, NJ, Vachon, CM, Ziv, E, Stram, DO, Hazelett, DJ, Haiman, CA & Cozen, W 2016, 'A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci', Cancer Epidemiology Biomarkers and Prevention, vol. 25, no. 12, pp. 1609-1618. https://doi.org/10.1158/1055-9965.EPI-15-1193

TY - JOUR

T1 - A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci

AU - Rand, Kristin A.

AU - Song, Chi

AU - Dean, Eric

AU - Serie, Daniel J.

AU - Curtin, Karen

AU - Sheng, Xin

AU - Hu, Donglei

AU - Huff, Carol Ann

AU - Bernal-Mizrachi, Leon

AU - Tomasson, H. Michael

AU - Ailawadhi, Sikander

AU - Singhal, Seema

AU - Pawlish, Karen

AU - Peters, Edward S.

AU - Bock, Cathryn H.

AU - Stram, Alex

AU - Van Den Berg, David J.

AU - Edlund, Christopher K.

AU - Conti, David V.

AU - Zimmerman, Todd

AU - Hwang, Amie E.

AU - Huntsman, Scott

AU - Graff, John

AU - Nooka, Ajay

AU - Kong, Yinfei

AU - Pregja, Silvana L.

AU - Berndt, Sonja I.

AU - Blot, William J.

AU - Carpten, John

AU - Casey, Graham

AU - Chu, Lisa

AU - Diver, W. Ryan

AU - Stevens, Victoria L.

AU - Lieber, Michael R.

AU - Goodman, Phyllis J.

AU - Hennis, Anselm J.M.

AU - Hsing, Ann W.

AU - Mehta, Jayesh

AU - Kittles, Rick A.

AU - Kolb, Suzanne

AU - Klein, Eric A.

AU - Leske, Cristina

AU - Murphy, Adam B.

AU - Nemesure, Barbara

AU - Neslund-Dudas, Christine

AU - Strom, Sara S.

AU - Vij, Ravi

AU - Rybicki, Benjamin A.

AU - Stanford, Janet L.

AU - Signorello, Lisa B.

AU - Witte, John S.

AU - Ambrosone, Christine B.

AU - Bhatti, Parveen

AU - John, Esther M.

AU - Bernstein, Leslie

AU - Zheng, Wei

AU - Olshan, Andrew F.

AU - Hu, Jennifer J.

AU - Ziegler, Regina G.

AU - Nyante, Sarah J.

AU - Bandera, Elisa V.

AU - Birmann, Brenda M.

AU - Ingles, Sue A.

AU - Press, Michael F.

AU - Atanackovic, Djordje

AU - Glenn, Martha J.

AU - Cannon-Albright, Lisa A.

AU - Jones, Brandt

AU - Tricot, Guido

AU - Martin, Thomas G.

AU - Kumar, Shaji K.

AU - Wolf, Jeffrey L.

AU - Deming Halverson, Sandra L.

AU - Rothman, Nathaniel

AU - Brooks-Wilson, Angela R.

AU - Rajkumar, S. Vincent

AU - Kolonel, Laurence N.

AU - Chanock, Stephen J.

AU - Slager, Susan L.

AU - Severson, Richard K.

AU - Janakiraman, Nalini

AU - Terebelo, Howard R.

AU - Brown, Elizabeth E.

AU - De Roos, Anneclaire J.

AU - Mohrbacher, Ann F.

AU - Colditz, Graham A.

AU - Giles, Graham G.

AU - Spinelli, John J.

AU - Chiu, Brian C.

AU - Munshi, Nikhil C.

AU - Anderson, Kenneth C.

AU - Levy, Joan

AU - Zonder, Jeffrey A.

AU - Orlowski, Robert Z.

AU - Lonial, Sagar

AU - Camp, Nicola J.

AU - Vachon, Celine M.

AU - Ziv, Elad

AU - Stram, Daniel O.

AU - Hazelett, Dennis J.

AU - Haiman, Christopher A.

AU - Cozen, Wendy

N1 - Funding Information: This study was supported by the National Cancer Institute at the NIH (1R01CA134786 to W. Cozen and Christopher A. Haiman; 2P50CA100707 to K.C. Anderson; Myeloma SPORE 2P50CA100707 Project 6 to K.C. Anderson, W. Cozen, and D.V. Conti; R01CA152336 and R01CA134674 to N.J. Camp; P50 CA142509 and R01CA184464 to R.Z. Orlowski; R21CA155951, R25CA76023, R01CA186646, U54CA118948 Project 3 and P30CA13148 (seed grant) to E.E. Brown; and R21CA191896 and K24CA169004 to E. Ziv). The study also received support from the Leukemia Lymphoma Society (LLS 6067-090) to N.J. Camp, the American Cancer Society (IRG60-001-47) to E.E. Brown, and the Steve and Nancy Grand Multiple Myeloma Translational Initiative to E. Ziv. Data collection from the cancer registries was supported by the National Cancer Institute Surveillance Epidemiology and End Results Population-based Registry Program, NIH, Department of Health and Human Services, under contracts N01-PC-35139 (to USC for Los Angeles County), HHSN 261201300021I, N01PC-2013- 00021 (to the New Jersey State Cancer Registry), and HHSN261201000026C (to the Utah Cancer Registry). Additional support for collection of incident multiple myeloma patient data was obtained from the Utah State Department of Health and the University of Utah, the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR), the National Program of Cancer Registries of the Centers for Disease Control and Prevention (5U58DP003931-02 to the New Jersey State Cancer Registry and 1U58DP000807-01 to the California Cancer Registry), the Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant, P30 CA42014 and by the USC Norris Comprehensive Cancer Center Core grant P30CA014089 from the National Cancer Institute. The collection of patients used in this publication was supported in part by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. AAPC studies: The MEC is supported by NIH grants CA63464, CA54281, CA1326792, CA148085, and HG004726. Genotyping of the PLCO samples was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH. LAAPC was funded by grant 99-00524V- 10258 from the Cancer Research Fund, under Interagency Agreement #97- 12013 (University of California contract #98-00924V) with the Department of Health Services Cancer Research Program. Cancer incidence data for the MEC and LAAPC studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with Federal funds from the NCI, NIH, Department of Health andHumanServices, under Contract No. N01- PC-35139, and the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant number 1U58DP000807-3 from the Centers for Disease Control and Prevention. KCPCS was supported by NIH grants CA056678, CA082664, and CA092579, with additional support from the Fred Hutchinson Cancer Research Center and the Intramural Program of the NationalHumanGenome Research Institute.MDAwas supported by grants, CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388. CaP Genes was supported by CA88164 and CA127298. SELECT was funded in part by Public Health Service grants U10 CA37429 (C.D. Blanke) and UM1 CA182883 (I.M. Thompson/C.M. Tangen) from the National Cancer Institute. GECAP was supported by NIH grant ES011126. SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt-Ingram Cancer Center (CA68485). AABC studies: AABC was supported by a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to CAH (W81XWH-08-1-0383), the Norris Foundation, P01-CA151135 and U19-CA148065. Each of the participating studies was supported by the following grants: MEC (NIH grants R01-CA63464, R37-CA54281 and UM1-CA164973); CARE (National Institute for Child Health and Development grant NO1-HD-3-3175, K05 CA136967); WCHS [U.S. Army Medical Research and Material Command (USAMRMC) grant DAMD-17-01-0-0334, the NIH grant R01-CA100598, and the Breast Cancer Research Foundation]; SFBCS (NIH grant R01-CA77305 and United States Army Medical Research Program grant DAMD17-96-6071); NC-BCFR (NIH grant U01-CA69417); CBCS (NIH Specialized Program of Research Excellence in Breast Cancer, grant number P50-CA58223, and Center for Environmental Health and Susceptibility National Institute of Environmental Health Sciences, NIH, grant number P30-ES10126); PLCO (Intramural Research Program, National Cancer Institute, NIH); NBHS (National Institutes of Health grant R01-CA100374); WFBC (NIH grant R01-CA73629). The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, NIH under RFA-CA-06-503 and through cooperative agreements withmembers of the Breast Cancer Family Registry and Principal Investigators. Publisher Copyright: © 2016 AACR.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry- European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 30 end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-kB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional.

AB - Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry- European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 30 end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-kB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional.

UR - http://www.scopus.com/inward/record.url?scp=85006255902&partnerID=8YFLogxK

U2 - 10.1158/1055-9965.EPI-15-1193

DO - 10.1158/1055-9965.EPI-15-1193

M3 - Article

C2 - 27587788

AN - SCOPUS:85006255902

SN - 1055-9965

VL - 25

SP - 1609

EP - 1618

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

IS - 12

ER -

A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci

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