Abstract
Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
| Original language | English (US) |
|---|---|
| Article number | 3166 |
| Journal | Nature communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2018 |
ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
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Identification of nine new susceptibility loci for endometrial cancer. / O’Mara, Tracy A.; Glubb, Dylan M.; Amant, Frederic; Annibali, Daniela; Ashton, Katie; Attia, John; Auer, Paul L.; Beckmann, Matthias W.; Black, Amanda; Bolla, Manjeet K.; Brauch, Hiltrud; Brenner, Hermann; Brinton, Louise; Buchanan, Daniel D.; Burwinkel, Barbara; Chang-Claude, Jenny; Chanock, Stephen J.; Chen, Chu; Chen, Maxine M.; Cheng, Timothy H.T.; Clarke, Christine L.; Clendenning, Mark; Cook, Linda S.; Couch, Fergus J.; Cox, Angela; Crous-Bous, Marta; Czene, Kamila; Day, Felix; Dennis, Joe; Depreeuw, Jeroen; Doherty, Jennifer Anne; Dörk, Thilo; Dowdy, Sean C.; Dürst, Matthias; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Friedenreich, Christine M.; Fritschi, Lin; Fung, Jenny; García-Closas, Montserrat; Gaudet, Mia M.; Giles, Graham G.; Goode, Ellen L.; Gorman, Maggie; Haiman, Christopher A.; Hall, Per; Hankison, Susan E.; Healey, Catherine S.; Hein, Alexander; Hillemanns, Peter; Hodgson, Shirley; Hoivik, Erling A.; Holliday, Elizabeth G.; Hopper, John L.; Hunter, David J.; Jones, Angela; Krakstad, Camilla; Kristensen, Vessela N.; Lambrechts, Diether; Marchand, Loic Le; Liang, Xiaolin; Lindblom, Annika; Lissowska, Jolanta; Long, Jirong; Lu, Lingeng; Magliocco, Anthony M.; Martin, Lynn; McEvoy, Mark; Meindl, Alfons; Michailidou, Kyriaki; Milne, Roger L.; Mints, Miriam; Montgomery, Grant W.; Nassir, Rami; Olsson, Håkan; Orlow, Irene; Otton, Geoffrey; Palles, Claire; Perry, John R.B.; Peto, Julian; Pooler, Loreall; Prescott, Jennifer; Proietto, Tony; Rebbeck, Timothy R.; Risch, Harvey A.; Rogers, Peter A.W.; Rübner, Matthias; Runnebaum, Ingo; Sacerdote, Carlotta; Sarto, Gloria E.; Schumacher, Fredrick; Scott, Rodney J.; Setiawan, V. Wendy; Shah, Mitul; Sheng, Xin; Shu, Xiao Ou; Southey, Melissa C.; Swerdlow, Anthony J.; Tham, Emma; Trovik, Jone; Turman, Constance; Tyrer, Jonathan P.; Vachon, Celine; VanDen Berg, David; Vanderstichele, Adriaan; Wang, Zhaoming; Webb, Penelope M.; Wentzensen, Nicolas; Werner, Henrica M.J.; Winham, Stacey J.; Wolk, Alicja; Xia, Lucy; Xiang, Yong Bing; Yang, Hannah P.; Yu, Herbert; Zheng, Wei; Pharoah, Paul D.P.; Dunning, Alison M.; Kraft, Peter; De Vivo, Immaculata; Tomlinson, Ian; Easton, Douglas F.; Spurdle, Amanda B.; Thompson, Deborah J.
In: Nature communications, Vol. 9, No. 1, 3166, 01.12.2018.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Identification of nine new susceptibility loci for endometrial cancer
AU - O’Mara, Tracy A.
AU - Glubb, Dylan M.
AU - Amant, Frederic
AU - Annibali, Daniela
AU - Ashton, Katie
AU - Attia, John
AU - Auer, Paul L.
AU - Beckmann, Matthias W.
AU - Black, Amanda
AU - Bolla, Manjeet K.
AU - Brauch, Hiltrud
AU - Brenner, Hermann
AU - Brinton, Louise
AU - Buchanan, Daniel D.
AU - Burwinkel, Barbara
AU - Chang-Claude, Jenny
AU - Chanock, Stephen J.
AU - Chen, Chu
AU - Chen, Maxine M.
AU - Cheng, Timothy H.T.
AU - Clarke, Christine L.
AU - Clendenning, Mark
AU - Cook, Linda S.
AU - Couch, Fergus J.
AU - Cox, Angela
AU - Crous-Bous, Marta
AU - Czene, Kamila
AU - Day, Felix
AU - Dennis, Joe
AU - Depreeuw, Jeroen
AU - Doherty, Jennifer Anne
AU - Dörk, Thilo
AU - Dowdy, Sean C.
AU - Dürst, Matthias
AU - Ekici, Arif B.
AU - Fasching, Peter A.
AU - Fridley, Brooke L.
AU - Friedenreich, Christine M.
AU - Fritschi, Lin
AU - Fung, Jenny
AU - García-Closas, Montserrat
AU - Gaudet, Mia M.
AU - Giles, Graham G.
AU - Goode, Ellen L.
AU - Gorman, Maggie
AU - Haiman, Christopher A.
AU - Hall, Per
AU - Hankison, Susan E.
AU - Healey, Catherine S.
AU - Hein, Alexander
AU - Hillemanns, Peter
AU - Hodgson, Shirley
AU - Hoivik, Erling A.
AU - Holliday, Elizabeth G.
AU - Hopper, John L.
AU - Hunter, David J.
AU - Jones, Angela
AU - Krakstad, Camilla
AU - Kristensen, Vessela N.
AU - Lambrechts, Diether
AU - Marchand, Loic Le
AU - Liang, Xiaolin
AU - Lindblom, Annika
AU - Lissowska, Jolanta
AU - Long, Jirong
AU - Lu, Lingeng
AU - Magliocco, Anthony M.
AU - Martin, Lynn
AU - McEvoy, Mark
AU - Meindl, Alfons
AU - Michailidou, Kyriaki
AU - Milne, Roger L.
AU - Mints, Miriam
AU - Montgomery, Grant W.
AU - Nassir, Rami
AU - Olsson, Håkan
AU - Orlow, Irene
AU - Otton, Geoffrey
AU - Palles, Claire
AU - Perry, John R.B.
AU - Peto, Julian
AU - Pooler, Loreall
AU - Prescott, Jennifer
AU - Proietto, Tony
AU - Rebbeck, Timothy R.
AU - Risch, Harvey A.
AU - Rogers, Peter A.W.
AU - Rübner, Matthias
AU - Runnebaum, Ingo
AU - Sacerdote, Carlotta
AU - Sarto, Gloria E.
AU - Schumacher, Fredrick
AU - Scott, Rodney J.
AU - Setiawan, V. Wendy
AU - Shah, Mitul
AU - Sheng, Xin
AU - Shu, Xiao Ou
AU - Southey, Melissa C.
AU - Swerdlow, Anthony J.
AU - Tham, Emma
AU - Trovik, Jone
AU - Turman, Constance
AU - Tyrer, Jonathan P.
AU - Vachon, Celine
AU - VanDen Berg, David
AU - Vanderstichele, Adriaan
AU - Wang, Zhaoming
AU - Webb, Penelope M.
AU - Wentzensen, Nicolas
AU - Werner, Henrica M.J.
AU - Winham, Stacey J.
AU - Wolk, Alicja
AU - Xia, Lucy
AU - Xiang, Yong Bing
AU - Yang, Hannah P.
AU - Yu, Herbert
AU - Zheng, Wei
AU - Pharoah, Paul D.P.
AU - Dunning, Alison M.
AU - Kraft, Peter
AU - De Vivo, Immaculata
AU - Tomlinson, Ian
AU - Easton, Douglas F.
AU - Spurdle, Amanda B.
AU - Thompson, Deborah J.
N1 - Funding Information: We thank the many individuals who participated in this study and the numerous institutions and their staff who supported recruitment, detailed in full in the Supplementary Information. The iCOGS and OncoArray endometrial cancer analysis were supported by NHMRC project grants (ID#1031333 and ID#1109286) to A.B.S., D.F.E., A.M.D., D.J.T., and I.T. A.B.S. (APP1061779), P.M.W., and T.A.O’. M. (APP1111246) are supported by the NHMRC Fellowship scheme. A.M.D. was supported by the Joseph Mitchell Trust. I.T. is supported by Cancer Research UK and the Oxford Comprehensive Biomedical Research Center. Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/ A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. OncoArray genotyping of ECAC cases was performed with the generous assistance of the Ovarian Cancer Association Consortium (OCAC). We particularly thank the efforts of Cathy Phelan. The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (Christopher I. Amos), U19-CA148112 (Thomas A. Sellers), R01-CA149429 (Catherine M. Phelan), and R01-CA058598 (Marc T. Goodman)); Canadian Institutes of Health Research (MOP-86727 (Linda E. Kelemen)); and the Ovarian Cancer Research Fund (Andrew Berchuck). CIDR genotyping for the Oncoarray was conducted under contract 268201200008I. OncoArray genotyping of the BCAC controls was funded by Genome Canada Grant GPH-129344, NIH Grant U19 CA148065, and Cancer UK Grant C1287/A16563. ANECS recruitment was supported by project grants from the NHMRC (ID#339435), The Cancer Council Queensland (ID#4196615), and Cancer Council Tasmania (ID#403031 and ID#457636). SEARCH recruitment was funded by a programme grant from Cancer Research UK (C490/A10124). Stage 1 and stage 2 case genotyping was supported by the NHMRC (ID#552402, ID#1031333). Control data were generated by the Wellcome Trust Case Control Consortium (WTCCC), and a full list of the investigators who contributed to the generation of the data is available from the WTCCC website. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02—funding for this project was provided by the Wellcome Trust under award 085475. NSECG was supported by the EU FP7 CHIBCHA grant, Wellcome Trust Centre for Human Genetics Core Grant 090532/Z/09Z, and CORGI was funded by Cancer Research UK. We thank Nick Martin, Dale Nyholt, and Anjali Henders for access to GWAS data from QIMR Controls. Recruitment of the QIMR controls was supported by the NHMRC. The University of Newcastle, the Gladys M Brawn Senior Research Fellowship scheme, The Vincent Fairfax Family Foundation, the Hunter Medical Research Institute, and the Hunter Area Pathology Service all contributed toward the costs of establishing the Hunter Community Study. The Bavarian Endometrial Cancer Study (BECS) was partly funded by the ELAN fund of the University of Erlangen. The Hannover-Jena Endometrial Cancer Study was partly supported by the Rudolf Bartling Foundation. The Leuven Endometrium Study (LES) was supported by the Verelst Foundation for endometrial cancer. The Mayo Endometrial Cancer Study (MECS) and Mayo controls (MAY) were supported by grants from the National Cancer Institute of United States Public Health Service (R01 CA122443, P30 CA15083, P50 CA136393, and GAME-ON the NCI Cancer Post-GWAS Initiative U19 CA148112), the Fred C and Katherine B Andersen Foundation, the Mayo Foundation, and the Ovarian Cancer Research Fund with support of the Smith family, in memory of Kathryn Sladek Smith. MoMaTEC received financial support from a Helse Vest Grant, the University of Bergen, Melzer Foundation, The Norwegian Cancer Society (Harald Andersens legat), The Research Council of Norway and Haukeland University Hospital. The Newcastle Endometrial Cancer Study (NECS) acknowledges contributions from the University of Newcastle, The NBN Children’s Cancer Research Group, Ms. Jennie Thomas, and the Hunter Medical Research Institute. RENDOCAS was supported through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet (numbers: 20110222, 20110483, 20110141 and DF07015), The Swedish Labor Market Insurance (number 100069), and The Swedish Cancer Society (number 11 0439). The Cancer Hormone Replacement Epidemiology in Sweden Study (CAHRES, formerly called The Singapore and Swedish Breast/Endometrial Cancer Study; SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institutes of Health, and the Susan G. Komen Breast Cancer Foundation. The WHI program is funded by the National Heart, Lung, and Blood Institute, the US National Institutes of Health, and the US Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C). This work was also funded by NCI U19 CA148065-01. The Nurses’ Health Study (NHS) is supported by the NCI, NIH Grants Number UM1 CA186107, P01 CA087969, R01 CA49449, 1R01 CA134958, and 2R01 CA082838. We thank the participants and staff of the Nurses’ Health Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. We assume full responsibility for analyses and interpretation of these data. We also thank Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School. Finally, we also acknowledge Pati Soule and Hardeep Ranu for their laboratory assistance. The Connecticut Endometrial Cancer Study was supported by NCI, NIH Grant Number RO1CA98346. The Fred Hutchinson Cancer Research Center (FHCRC) is supported by NCI, NIH Grant Number NIH RO1 CA105212, RO1 CA 87538, RO1 CA75977, RO3 CA80636, NO1 HD23166, R35 CA39779, KO5 CA92002, and funds from the Fred Hutchinson Cancer Research Center. The Multiethnic Cohort Study (MEC) is supported by the NCI, NHI Grants Number CA54281, CA128008, and 2R01 CA082838. The California Teachers Study (CTS) is supported by NCI, NIH Grant Number 2R01 CA082838, R01 CA91019, and R01 CA77398, and contract 97-10500 from the California Breast Cancer Research Fund. The Polish Endometrial Cancer Study (PECS) is supported by the Intramural Research Program of the NCI. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) is supported by the Extramural and the Intramural Research Programs of the NCI. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts, HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. This manuscript was prepared in collaboration with investigators of the WHI, and has been reviewed and/or approved by the Women’s Health Initiative (WHI). WHI investigators are listed at https://www.whi. org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator% 20Short%20List.pdf. The Breast Cancer Association Consortium (BCAC) is funded by Cancer Research UK (C1287/A10118, C1287/A12014). The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07), and the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge. This research has been conducted using the UK Biobank Resource under applications 5122 and 9797. We gratefully acknowledge the TCGA endometrial cancer consortium for providing samples, tissues, data processing, and making data and results available. Additional funding for individual control groups is detailed in the Supplementary Information.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
AB - Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
UR - http://www.scopus.com/inward/record.url?scp=85051554034&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85051554034&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-05427-7
DO - 10.1038/s41467-018-05427-7
M3 - Article
C2 - 30093612
AN - SCOPUS:85051554034
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3166
ER -