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A Meta-Analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci

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A Meta-Analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci Published OnlineFirst September 1, 2016; DOI: 10.1158/1055-9965.EPI-15-1193 Research Article Cancer Epidemiology, Biomarkers A Meta-analysis of Multiple Myeloma Risk Regions & Prevention in African and European Ancestry Populations Identifies Putatively Functional Loci Kristin A. Rand1,ChiSong1, Eric Dean2,DanielJ.Serie3, Karen Curtin4, Xin Sheng1, Donglei Hu5, Carol Ann Huff6, Leon Bernal-Mizrachi7,MichaelH.Tomasson8, Sikander Ailawadhi3, Seema Singhal9, Karen Pawlish10, Edward S. Peters11, Cathryn H. Bock12,AlexStram13,DavidJ.VanDenBerg1, Christopher K. Edlund1, David V. Conti1,ToddZimmerman14,AmieE.Hwang1, Scott Huntsman5,JohnGraff15, Ajay Nooka7, Yinfei Kong1, Silvana L. Pregja12, Sonja I. Berndt16, William J. Blot17,18, John Carpten19,GrahamCasey1,LisaChu20,21,W.RyanDiver22,VictoriaL.Stevens22, Michael R. Lieber1, Phyllis J. Goodman23, Anselm J.M. Hennis24,25, Ann W. Hsing21, Jayesh Mehta9, Rick A. Kittles26, Suzanne Kolb27,EricA.Klein28,CristinaLeske24, Adam B. Murphy9, Barbara Nemesure24, Christine Neslund-Dudas29,SaraS.Strom30, Ravi Vij8, Benjamin A. Rybicki29, Janet L. Stanford27, Lisa B. Signorello31,JohnS.Witte32, Christine B. Ambrosone33, Parveen Bhatti27,EstherM.John20,21, Leslie Bernstein34, Wei Zheng17, Andrew F. Olshan35,JenniferJ.Hu36,ReginaG.Ziegler16, Sarah J. Nyante35, Elisa V. Bandera15,BrendaM.Birmann31, Sue A. Ingles1, Michael F. Press1, Djordje Atanackovic4, Martha J. Glenn4, Lisa A. Cannon-Albright4, Brandt Jones4, Guido Tricot37, Thomas G. Martin5, Shaji K. Kumar38,JeffreyL.Wolf5, Sandra L. Deming Halverson17, Nathaniel Rothman16, Angela R. Brooks-Wilson39, S. Vincent Rajkumar38, Laurence N. Kolonel40, Stephen J. Chanock16, Susan L. Slager38, Richard K. Severson12, Nalini Janakiraman29, Howard R. Terebelo41, Elizabeth E. Brown42, Anneclaire J. De Roos43, Ann F. Mohrbacher1,GrahamA.Colditz8,GrahamG.Giles44,45,46, John J. Spinelli39,47, Brian C. Chiu14,NikhilC.Munshi48, Kenneth C. Anderson48, Joan Levy49, Jeffrey A. Zonder12,RobertZ.Orlowski30,SagarLonial7, Nicola J.Camp4,Celine M.Vachon38, Elad Ziv5, Daniel O. Stram1, Dennis J. Hazelett50, Christopher A. Haiman1,andWendyCozen1 Abstract Background: Genome-wide association studies (GWAS) in correlated variants clustered within the gene body of ULK4. European populations have identified genetic risk variants asso- Correlated variants in 7p15.3 clustered around an enhancer at ciated with multiple myeloma. the 30 end of the CDCA7L transcription termination site. A Methods: We performed association testing of common vari- missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; À ation in eight regions in 1,318 patients with multiple myeloma P ¼ 2.93 Â 10 7)inTNFRSF13B encodes a lymphocyte-specific and 1,480 controls of European ancestry and 1,305 patients with protein in the TNF receptor family that interacts with the NF-kB multiple myeloma and 7,078 controls of African ancestry and pathway. SNPs correlated with the index signal in 22q13.1 cluster conducted a meta-analysis to localize the signals, with epigenetic around the promoter and enhancer regions of CBX7. annotation used to predict functionality. Conclusions: We found that reported multiple myeloma Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 susceptibility regions contain risk variants important across were statistically significantly (P < 0.05) associated with multiple populations, supporting the use of multiple racial/ethnic myeloma risk in persons of African ancestry and persons of groups with different underlying genetic architecture to European ancestry, and the variant in 3p22.1 was associated enhance the localization and identification of putatively func- in European ancestry only. In a combined African ancestry– tional alleles. European ancestry meta-analysis, variation in five regions Impact: A subset of reported risk loci for multiple myeloma has (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically sig- consistent effects across populations and is likely to be functional. nificantly associated with multiple myeloma risk. In 3p22.1, the Cancer Epidemiol Biomarkers Prev; 25(12); 1609–18. Ó2016 AACR. 1Keck School of Medicine of USC and Norris Comprehensive Cancer Center, Francisco, California. 6Johns Hopkins School of Medicine, Johns Hopkins Uni- University of Southern California, Los Angeles, California. 2Sutter Health, Oak- versity, Baltimore, Maryland. 7Winship Cancer Institute, Emory University, land, California. 3Mayo Clinic, Jacksonville, Florida. 4University of Utah School of Atlanta, Georgia. 8Alvin J. Siteman Cancer Center, Washington University School Medicine, Salt Lake City, Utah. 5University of California at San Francisco, San of Medicine, Washington University, St. Louis, Missouri. 9Robert H. Lurie Cancer www.aacrjournals.org 1609 Downloaded from cebp.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst September 1, 2016; DOI: 10.1158/1055-9965.EPI-15-1193 Rand et al. Introduction study also replicated 6 of the 7 known regions for multiple myeloma risk (8). Multiple myeloma, a neoplasm of malignant plasma cells For common susceptibility alleles shared across populations, arising in bone marrow, comprises 1.9% of all cancer deaths and underlying genetic differences in linkage disequilibrium (LD) 20% of all hematologic cancer deaths (www.seer.ca.gov; ref. 1). across racial/ethnic groups can be leveraged to more precisely Multiple myeloma is uncommon, with an age-adjusted incidence localize markers of disease risk (9). In the present study, we rate of 7.9 per 100,000 in males and 5.1 per 100,000 in females in examined multiple myeloma susceptibility regions for indivi- the United States in 2012 (www.seer.cancer.gov; ref. 1). Clinical duals from North America of African and European ancestry and manifestations range from asymptomatic (smoldering) myeloma conducted GWAS plus imputation-based fine mapping in an to active symptomatic disease (2). There is a 2- to 3-fold higher attempt to identify putative functional variants that better capture risk of disease in African Americans compared with individuals risk in these populations. of European origin and a 2-fold increased risk in relatives of multiple myeloma cases (3, 4), suggesting a heritable component Materials and Methods to this cancer. A genome-wide association study (GWAS) of 1,675 cases and Ethics statement 5,903 controls from a Northern European population identified 2 All studies had approval from their respective Institutional genome-wide significant novel loci associated with multiple mye- Review Boards according to the Declaration of Helsinki Ethical loma risk at 3p22.1 (rs1052501) and 7p15.3 (rs4487645), as well Principles for Medical Research Involving Human Subjects in À as a suggestive association (P 10 7)at2p23.3 (rs6746082; ref. 5). 1964. Signed informed consent was obtained from all partici- In a second GWAS of 4,692 cases and 10,990 controls from the pants at the time of blood/saliva collection. The participants in United Kingdom and Germany, 4 additional genome-wide signi- this study were recruited at multiple sites described below. ficant risk loci were identified at 3q26.2 (rs10936599), 6p21.33 (rs2285803),17p11.2(rs4273077),and 22q13.1(rs877529;ref.6). African ancestry study participants For these common risk variants, the per allele ORs and risk allele Study participants included 1,150 African ancestry patients frequencies (RAF) ranged from 1.19 to 1.39 and 0.11 to 0.76, with multiple myeloma enrolled in the phase 1 collection respectively. In a European study involving a large multiple mye- (through November 11, 2014) of the African American Multiple loma consortium, 3 of these regions (2p23.3, 3p22.1, and 7p15.3) Myeloma Study (AAMMS) from 11 clinical centers [Winship replicated at P < 0.05 (7). In the most recent published GWAS, Cancer Institute and Grady Memorial Hospital at Emory Univer- the 2q12.3 region was implicated in multiple myeloma risk in a sity (Atlanta, GA), MD Anderson Cancer Center at University of discovery set of 972 cases and 1,064 controls of European Texas (Houston, TX), Robert H. Lurie Comprehensive Cancer origin and was replicated in a similar set of 297 cases (8). This Center at Northwestern University (Chicago, IL), Sidney Kimmel Center, Northwestern University, Chicago, Illinois. 10New Jersey State Cancer University of Hawaii, Honolulu, Hawaii. 41Providence Hospital, Southfield, Michi- Registry, New Jersey Department of Health, Trenton, New Jersey. 11Louisiana gan. 42University of Alabama at Birmingham, Birmingham, Alabama. 43School of State University School of Public Health, Louisiana State University, New Public Health, Drexel University, Philadelphia, Pennsylvania. 44Cancer Epidemi- Orleans, Louisiana. 12Karmanos Cancer Institute and Department of Oncology, ology Centre, Cancer Council of Victoria, Melbourne, Victoria, Australia. 45School Wayne State University School of Medicine, Detroit, Michigan. 13Genomic Health, of Population and Global Health, Centre for Epidemiology and Biostatistics, Inc., Redwood City, California. 14University of Chicago, Chicago, Illinois. 15Rut- University of Melbourne, Melbourne, Victoria, Australia. 46Monash University, gers-Robert Wood Johnson Medical School, Rutgers State University of New Melbourne, Melbourne, Victoria, Australia. 47School of Population and Public Jersey, New Brunswick, New Jersey. 16Division of Cancer Epidemiology and Health, University of British Columbia, Vancouver, Canada. 48Dana Farber Genetics, National Cancer Institute, U.S. NIH, Bethesda,
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