GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer

Maxine M Chen¹, Tracy A O'Mara², Deborah J Thompson³, Jodie N Painter²; Australian National Endometrial Cancer Study Group (ANECS); John Attia^{4

5}, Amanda Black⁶, Louise Brinton⁶, Stephen Chanock⁶, Chu Chen⁷, Timothy Ht Cheng⁸, Linda S Cook^{9

10}, Marta Crous-Bou^{1

11}, Jennifer Doherty¹², Christine M Friedenreich¹³, Montserrat Garcia-Closas^{6

14}, Mia M Gaudet¹⁵, Maggie Gorman⁸, Christopher Haiman¹⁶, Susan E Hankinson^{11

17}, Patricia Hartge⁶, Brian E Henderson¹⁶, Shirley Hodgson¹⁸, Elizabeth G Holliday⁴, Pamela L Horn-Ross¹⁹, David J Hunter¹, Loic Le Marchand²⁰, Xiaolin Liang²¹, Jolanta Lissowska²², Jirong Long²³, Lingeng Lu²⁴, Anthony M Magliocco²⁵, Lynn Martin⁸, Mark McEvoy⁵; National Study Of Endometrial Cancer Genetics Group (NSECG); Sara H Olson²¹, Irene Orlow²¹, Loreall Pooler¹⁶, Jennifer Prescott¹¹, Radhai Rastogi²¹, Timothy R Rebbeck²⁶, Harvey Risch²⁴, Carlotta Sacerdote^{27

28}, Frederick Schumacher¹⁶, Veronica Wendy Setiawan¹⁶, Rodney J Scott^{4

29

30}, Xin Sheng¹⁶, Xiao-Ou Shu²³, Constance Turman¹, David Van Den Berg¹⁶, Zhaoming Wang⁶, Noel S Weiss³¹, Nicholas Wentzensen⁶, Lucy Xia¹⁶, Yong-Bing Xiang³², Hannah P Yang⁶, Herbert Yu²⁰, Wei Zheng²³, Paul D P Pharoah³³, Alison M Dunning³³, Ian Tomlinson³, Douglas F Easton^{3

33}, Peter Kraft¹, Amanda B Spurdle², Immaculata De Vivo^{34

11}

Affiliations

¹ Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA 02115, USA.
² Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia.
³ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
⁴ Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW 2305, Australia.
⁵ School of Medicine and Public Health, Centre for Clinical Epidemiology and Biostatistics, University of Newcastle, Newcastle, NSW 2308, Australia.
⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
⁷ Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁸ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁹ University of New Mexico, Albuquerque, NM 87131, USA.
¹⁰ Division of Cancer Care, Department of Population Health Research, Alberta Health Services, Calgary, AB, Canada.
¹¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹² Geisel School of Medicine, Dartmouth College, Lebanon, NH 03755, USA.
¹³ Department of Cancer Epidemiology and Prevention Research, Cancer Control Alberta, Alberta Health Services, Calgary, AB, Canada.
¹⁴ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹⁵ Epidemiology Research Program, American Cancer Society, Atlanta, GA 30329, USA.
¹⁶ University of Southern California, Los Angeles, CA 90033, USA.
¹⁷ Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst MA 01003, USA.
¹⁸ Department of Clinical Genetics, St George's, University of London, London SW17 0RE, UK.
¹⁹ Cancer Prevention Institute of California, Fremont, CA 94538, USA.
²⁰ University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
²¹ Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
²² Department of Cancer Epidemiology and Prevention, M Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland.
²³ Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt - Ingram Cancer Center, Vanderbilt University Medical Center, Nashville TN 27232, USA.
²⁴ Yale University School of Public Health, New Haven, CT 06510, USA.
²⁵ H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
²⁶ Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
²⁷ Center for Cancer Prevention (CPO-Piemonte), Turin, Italy.
²⁸ Human Genetic Foundation (HuGeF), Turin, Italy.
²⁹ Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW 2305, Australia.
³⁰ School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW 2308, Australia.
³¹ University of Washington, Seattle, WA 19024, USA.
³² Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China and.
³³ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
³⁴ Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA 02115, USA, nhidv@channing.harvard.edu.

PMID: 27008869
PMCID: PMC5868213
DOI: 10.1093/hmg/ddw092

Meta-Analysis

GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer

Maxine M Chen et al. Hum Mol Genet. 2016.

. 2016 Jun 15;25(12):2612-2620.

doi: 10.1093/hmg/ddw092. Epub 2016 Mar 23.

Authors

Affiliations

¹ Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA 02115, USA.
² Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia.
³ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
⁴ Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW 2305, Australia.
⁵ School of Medicine and Public Health, Centre for Clinical Epidemiology and Biostatistics, University of Newcastle, Newcastle, NSW 2308, Australia.
⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
⁷ Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁸ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁹ University of New Mexico, Albuquerque, NM 87131, USA.
¹⁰ Division of Cancer Care, Department of Population Health Research, Alberta Health Services, Calgary, AB, Canada.
¹¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹² Geisel School of Medicine, Dartmouth College, Lebanon, NH 03755, USA.
¹³ Department of Cancer Epidemiology and Prevention Research, Cancer Control Alberta, Alberta Health Services, Calgary, AB, Canada.
¹⁴ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹⁵ Epidemiology Research Program, American Cancer Society, Atlanta, GA 30329, USA.
¹⁶ University of Southern California, Los Angeles, CA 90033, USA.
¹⁷ Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst MA 01003, USA.
¹⁸ Department of Clinical Genetics, St George's, University of London, London SW17 0RE, UK.
¹⁹ Cancer Prevention Institute of California, Fremont, CA 94538, USA.
²⁰ University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
²¹ Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
²² Department of Cancer Epidemiology and Prevention, M Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland.
²³ Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt - Ingram Cancer Center, Vanderbilt University Medical Center, Nashville TN 27232, USA.
²⁴ Yale University School of Public Health, New Haven, CT 06510, USA.
²⁵ H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
²⁶ Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
²⁷ Center for Cancer Prevention (CPO-Piemonte), Turin, Italy.
²⁸ Human Genetic Foundation (HuGeF), Turin, Italy.
²⁹ Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW 2305, Australia.
³⁰ School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW 2308, Australia.
³¹ University of Washington, Seattle, WA 19024, USA.
³² Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China and.
³³ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
³⁴ Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA 02115, USA, nhidv@channing.harvard.edu.

PMID: 27008869
PMCID: PMC5868213
DOI: 10.1093/hmg/ddw092

Abstract

Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 ^-⁸) at 6p22.3 (rs1740828; P = 2.29 × 10 ^-⁸, OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.

PubMed Disclaimer

Figures

**Figure 1**
Manhattan plot of meta-analysis results for EC in four cohorts. Association results between imputed and genotyped SNPs and risk of EC in women of European ancestry are depicted. Dashed line indicates the log of the threshold for genome-wide significance (P < 5.0 × 10 ⁻⁸).

**Figure 2**
Forest plots of the odds ratios for the association between rs2797160, rs1740828, rs9600103, rs11651052 and EC.

**Figure 3**
Regional association plot of 6p22.3 with annotation of genomic features, likely enhancers, and target genes. Association results for all SNPs in the 6p22.3 locus with EC risk from the meta-analysis are shown in the first panel. SNPs are plotted as the negative log of the P-value against relative position across the locus (base position [hg19] displayed across the top). The lead SNP, rs1740828, is shown as a red filled diamond. LD with surrounding SNPs are indicated by color (SNPs 0.5 ≤ r²< 0.8 are orange, 0.2 ≤ r² <0.5 are yellow, and r²< 0.2 are unfilled). There were no SNPs with an r²≥ 0.8 to the lead SNP. The second panel displays genes as identified by RefSeq. Likely enhancers predicted by Hnisz *et al.* (23) and PreSTIGE (24) that overlap SNPs in LD (r²> 0.2) with the lead SNP are depicted as colored bars, where the color matches the schematic of its predicted target gene (the black bar is predicted to target *CDKAL1*, not shown in this figure). Histone modification associated with promoters (H3K4Me1) and enhancers (H3K4Me1 and H3K27Ac) from seven ENCODE Project cell types and DNaseI hypersensitivity sites (DHS) and transcription factor (TF) binding sites identified in 125 and 91 ENCODE Project cell types, respectively, are also displayed.

See this image and copyright information in PMC

References

1. Ferlay J., Soerjomataram I., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray F. (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 136, E359–E386. - PubMed
1. Howlader N., Noone A.M., Krapcho M., Garshell J., Miller D., Altekruse S.F., Kosary C.L., Yu M., Ruhl J., Tatalovich Z. et al. (eds). (2014) SEER Cancer Statistics Review, 1975-2012. National Cancer Institute. Bethesda, MD.
1. Duncan M.E., Seagroatt V., Goldacre M.J. (2012) Cancer of the body of the uterus: trends in mortality and incidence in England, 1985-2008. BJOG, 119, 333–339. - PubMed
1. Wartko P., Sherman M.E., Yang H.P., Felix A.S., Brinton L.A., Trabert B. (2013) Recent changes in endometrial cancer trends among menopausal-age U.S. women. Cancer Epidemiol., 37, 374–377. - PMC - PubMed
1. Hemminki K., Vaittinen P., Dong C. (1999) Endometrial cancer in the family-cancer database. Cancer Epidemiol. Biomarkers Prev., 8, 1005–1010. - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer

Affiliations

GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources