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Cancer Epidemiol Biomarkers Prev. 2016 Dec;25(12):1609-1618. Epub 2016 Sep 1.

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

Author information

1
Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
2
Sutter Health, Oakland, California.
3
Mayo Clinic, Jacksonville, Florida.
4
University of Utah School of Medicine, Salt Lake City, Utah.
5
University of California at San Francisco, San Francisco, California.
6
Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland.
7
Winship Cancer Institute, Emory University, Atlanta, Georgia.
8
Alvin J. Siteman Cancer Center, Washington University School of Medicine, Washington University, St. Louis, Missouri.
9
Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois.
10
New Jersey State Cancer Registry, New Jersey Department of Health, Trenton, New Jersey.
11
Louisiana State University School of Public Health, Louisiana State University, New Orleans, Louisiana.
12
Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
13
Genomic Health, Inc., Redwood City, California.
14
University of Chicago, Chicago, Illinois.
15
Rutgers-Robert Wood Johnson Medical School, Rutgers State University of New Jersey, New Brunswick, New Jersey.
16
Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland.
17
International Epidemiology Institute, Rockville, Maryland.
18
Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
19
The Translational Genomics Research Institute, Phoenix, Arizona.
20
Cancer Prevention Institute of California, Fremont, California.
21
Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, California.
22
American Cancer Society, Atlanta, Georgia.
23
SWOG Statistical Center, Seattle, Washington.
24
Stony Brook University, Stony Brook, New York.
25
Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados.
26
Department of Surgery, University of Arizona, Tucson, Arizona.
27
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
28
Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, Ohio.
29
Henry Ford Hospital, Detroit, Michigan.
30
The University of Texas MD Anderson Cancer Center, University of Texas, Houston, Texas.
31
Harvard School of Public Health, Harvard University, Boston, Massachusetts.
32
Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
33
Roswell Park Cancer Institute, Buffalo, New York.
34
Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, California.
35
Gillings School of Global Public Health, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
36
Sylvester Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, Florida.
37
University of Iowa, Iowa City, Iowa.
38
Mayo Clinic, Rochester, Minnesota.
39
BC Cancer Agency, Vancouver, Canada.
40
University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii.
41
Providence Hospital, Southfield, Michigan.
42
University of Alabama at Birmingham, Birmingham, Alabama.
43
School of Public Health, Drexel University, Philadelphia, Pennsylvania.
44
Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Victoria, Australia.
45
School of Population and Global Health, Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia.
46
Monash University, Melbourne, Melbourne, Victoria, Australia.
47
School of Population and Public Health, University of British Columbia, Vancouver, Canada.
48
Dana Farber Cancer Institute, Harvard School of Medicine, Harvard University, Boston, Massachusetts.
49
Multiple Myeloma Research Foundation, Norwalk, Connecticut.
50
Center for Bioinformatics and Computational Biology, Cedars Sinai Medical Center, Los Angeles, California. wcozen@usc.edu haiman@usc.edu Dennis.Hazelett@csmc.edu.
51
Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. wcozen@usc.edu haiman@usc.edu Dennis.Hazelett@csmc.edu.

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 3' 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-κB 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. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.

PMID:
27587788
PMCID:
PMC5524541
DOI:
10.1158/1055-9965.EPI-15-1193
[Indexed for MEDLINE]
Free PMC Article

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