Cross-cancer pleiotropic analysis of endometrial cancer: PAGE and E2C2 consortia.
Genome-wide association studies (GWAS) have identified a large number of cancer-associated single nucleotide polymorphisms (SNPs), several of which have been associated with multiple cancer sites suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesized that SNPs associated with other cancers may be additionally associated with endometrial cancer. We examined 213 SNPs previously associated with 14 other cancers for their associations with endometrial cancer in 3758 endometrial cancer cases and 5966 controls of European ancestry from two consortia: Population Architecture Using Genomics and Epidemiology and the Epidemiology of Endometrial Cancer Consortium. Study-specific logistic regression estimates adjusted for age, body mass index and the most significant principal components of genetic ancestry were combined using fixed-effect meta-analysis to evaluate the association between each SNP and endometrial cancer risk. A Bonferroni-corrected P value of 2.35×10(-4) was used to determine statistical significance of the associations. SNP rs7679673, ~6.3kb upstream of TET2 and previously reported to be associated with prostate cancer risk, was associated with endometrial cancer risk in the direction opposite to that for prostate cancer [meta-analysis odds ratio = 0.87 (per copy of the C allele), 95% confidence interval = 0.81, 0.93; P = 7.37×10(-5)] with no evidence of heterogeneity across studies (P heterogeneity = 0.66). This pleiotropic analysis is the first to suggest TET2 as a susceptibility locus for endometrial cancer.
Department of Preventive Medicine, Keck School of Medicine, and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37235, USA, National Cancer Institute, Bethesda, MD 20892, USA, M.Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland, Cancer Prevention Institute of California, Fremont, CA 94538, USA, Institute of Population Based Cancer Research, Cancer Registry of Norway, N-0304 Oslo, Norway, Division of Cancer Etiology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA, Department of Epidemiology, Yale School of Public Health, New Haven CT 06520, USA, Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Division of Research, Kaiser Permanente Northern California, Oakland, CA 94611, USA, Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03756, USA, Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, OH 43210, USA, Department of Obstetrics and Gynecology, University of California, Davis, CA 95616, USA, Department of Oncology, Wayne State University School of Medicine and Population Studies and Disparities Research, Karmanos Cancer Institute, Detroit, MI 48202, USA and Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA vsetiawa@usc.edu.
Veronica Wendy
VW
Setiawan
Department of Preventive Medicine, Keck School of Medicine, and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37235, USA, National Cancer Institute, Bethesda, MD 20892, USA, M.Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland, Cancer Prevention Institute of California, Fremont, CA 94538, USA, Institute of Population Based Cancer Research, Cancer Registry of Norway, N-0304 Oslo, Norway, Division of Cancer Etiology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA, Department of Epidemiology, Yale School of Public Health, New Haven CT 06520, USA, Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Division of Research, Kaiser Permanente Northern California, Oakland, CA 94611, USA, Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03756, USA, Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, OH 43210, USA, Department of Obstetrics and Gynecology, University of California, Davis, CA 95616, USA, Department of Oncology, Wayne State University School of Medicine and Population Studies and Disparities Research, Karmanos Cancer Institute, Detroit, MI 48202, USA and Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
Fredrick
F
Schumacher
Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Jennifer
J
Prescott
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Jeffrey
J
Haessler
Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37235, USA.
Jennifer
J
Malinowski
National Cancer Institute, Bethesda, MD 20892, USA.
Nicolas
N
Wentzensen
National Cancer Institute, Bethesda, MD 20892, USA.
Hannah
H
Yang
National Cancer Institute, Bethesda, MD 20892, USA.
Stephen
S
Chanock
National Cancer Institute, Bethesda, MD 20892, USA.
Louise
L
Brinton
National Cancer Institute, Bethesda, MD 20892, USA.
Patricia
P
Hartge
M.Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland.
Jolanta
J
Lissowska
Department of Preventive Medicine, Keck School of Medicine, and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37235, USA, National Cancer Institute, Bethesda, MD 20892, USA, M.Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland, Cancer Prevention Institute of California, Fremont, CA 94538, USA, Institute of Population Based Cancer Research, Cancer Registry of Norway, N-0304 Oslo, Norway, Division of Cancer Etiology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA, Department of Epidemiology, Yale School of Public Health, New Haven CT 06520, USA, Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Division of Research, Kaiser Permanente Northern California, Oakland, CA 94611, USA, Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03756, USA, Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, OH 43210, USA, Department of Obstetrics and Gynecology, University of California, Davis, CA 95616, USA, Department of Oncology, Wayne State University School of Medicine and Population Studies and Disparities Research, Karmanos Cancer Institute, Detroit, MI 48202, USA and Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
S Lani
SL
Park
Cancer Prevention Institute of California, Fremont, CA 94538, USA.
Iona
I
Cheng
Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37235, USA.
William S
WS
Bush
Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37235, USA.
Dana C
DC
Crawford
Institute of Population Based Cancer Research, Cancer Registry of Norway, N-0304 Oslo, Norway.
Giske
G
Ursin
Cancer Prevention Institute of California, Fremont, CA 94538, USA.
Pamela
P
Horn-Ross
Division of Cancer Etiology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Leslie
L
Bernstein
Department of Epidemiology, Yale School of Public Health, New Haven CT 06520, USA.
Lingeng
L
Lu
Department of Epidemiology, Yale School of Public Health, New Haven CT 06520, USA.
Harvey
H
Risch
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
Herbert
H
Yu
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Division of Research, Kaiser Permanente Northern California, Oakland, CA 94611, USA.
Lori C
LC
Sakoda
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03756, USA.
Jennifer
J
Doherty
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Chu
C
Chen
Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, OH 43210, USA.
Rebecca
R
Jackson
Department of Obstetrics and Gynecology, University of California, Davis, CA 95616, USA.
Shagufta
S
Yasmeen
Department of Oncology, Wayne State University School of Medicine and Population Studies and Disparities Research, Karmanos Cancer Institute, Detroit, MI 48202, USA and.
Michele
M
Cote
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Jonathan M
JM
Kocarnik
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Ulrike
U
Peters
Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
Peter
P
Kraft
Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
Immaculata
I
De Vivo
Department of Preventive Medicine, Keck School of Medicine, and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37235, USA, National Cancer Institute, Bethesda, MD 20892, USA, M.Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland, Cancer Prevention Institute of California, Fremont, CA 94538, USA, Institute of Population Based Cancer Research, Cancer Registry of Norway, N-0304 Oslo, Norway, Division of Cancer Etiology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA, Department of Epidemiology, Yale School of Public Health, New Haven CT 06520, USA, Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Division of Research, Kaiser Permanente Northern California, Oakland, CA 94611, USA, Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03756, USA, Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, OH 43210, USA, Department of Obstetrics and Gynecology, University of California, Davis, CA 95616, USA, Department of Oncology, Wayne State University School of Medicine and Population Studies and Disparities Research, Karmanos Cancer Institute, Detroit, MI 48202, USA and Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
Christopher A
CA
Haiman
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Charles
C
Kooperberg
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
Loic
L
Le Marchand
D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012307:Risk Factors
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human