Abstract
Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (r g = 0.23, P = 9.3 × 10 −3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10 −3 ) and concordance in effect direction (P = 2.0 × 10 −3 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10 −5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10 −8 , OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 1978-1987 |
| Number of pages | 10 |
| Journal | Cancer Medicine |
| Volume | 7 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 2018 |
| Externally published | Yes |
Keywords
- Cross-disease analysis
- endometrial cancer
- endometriosis
- genetic correlation
- genome-wide association study
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In: Cancer Medicine, Vol. 7, No. 5, 05.2018, p. 1978-1987.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Genetic overlap between endometriosis and endometrial cancer
T2 - evidence from cross-disease genetic correlation and GWAS meta-analyses
AU - Painter, Jodie N.
AU - O'Mara, Tracy A.
AU - Morris, Andrew P.
AU - Cheng, Timothy H.T.
AU - Gorman, Maggie
AU - Martin, Lynn
AU - Hodson, Shirley
AU - Jones, Angela
AU - Martin, Nicholas G.
AU - Gordon, Scott
AU - Henders, Anjali K.
AU - Attia, John
AU - McEvoy, Mark
AU - Holliday, Elizabeth G.
AU - Scott, Rodney J.
AU - Webb, Penelope M.
AU - Fasching, Peter A.
AU - Beckmann, Matthias W.
AU - Ekici, Arif B.
AU - Hein, Alexander
AU - Rübner, Matthias
AU - Hall, Per
AU - Czene, Kamila
AU - Dörk, Thilo
AU - Dürst, Matthias
AU - Hillemanns, Peter
AU - Runnebaum, Ingo
AU - Lambrechts, Diether
AU - Amant, Frederic
AU - Annibali, Daniela
AU - Depreeuw, Jeroen
AU - Vanderstichele, Adriaan
AU - Goode, Ellen L.
AU - Cunningham, Julie M.
AU - Dowdy, Sean C.
AU - Winham, Stacey J.
AU - Trovik, Jone
AU - Hoivik, Erling
AU - Werner, Henrica M.J.
AU - Krakstad, Camilla
AU - Ashton, Katie
AU - Otton, Geoffrey
AU - Proietto, Tony
AU - Tham, Emma
AU - Mints, Miriam
AU - Ahmed, Shahana
AU - Healey, Catherine S.
AU - Shah, Mitul
AU - Pharoah, Paul D.P.
AU - Dunning, Alison M.
AU - Dennis, Joe
AU - Bolla, Manjeet K.
AU - Michailidou, Kyriaki
AU - Wang, Qin
AU - Tyrer, Jonathan P.
AU - Hopper, John L.
AU - Peto, Julian
AU - Swerdlow, Anthony J.
AU - Burwinkel, Barbara
AU - Brenner, Hermann
AU - Meindl, Alfons
AU - Brauch, Hiltrud
AU - Lindblom, Annika
AU - Chang-Claude, Jenny
AU - Couch, Fergus J.
AU - Giles, Graham G.
AU - Kristensen, Vessela N.
AU - Cox, Angela
AU - Zondervan, Krina T.
AU - Nyholt, Dale R.
AU - MacGregor, Stuart
AU - Montgomery, Grant W.
AU - Tomlinson, Ian
AU - Easton, Douglas F.
AU - Thompson, Deborah J.
AU - Spurdle, Amanda B.
N1 - Funding Information: We acknowledge with appreciation all women who participated in the QIMR Berghofer Medical Research Institute and OXGENE endometriosis studies and the ANECS-SEARCH, NSECG, and iCOGS endometrial cancer studies. For the endometriosis study, we thank Endometriosis Associations for supporting study recruitment, and the many hospital directors and staff, gynecologists, general practitioners, and pathology services in Australia and the UK who provided assistance with blood collection and confirming diagnoses. We are grateful to the many research assistants and interviewers for assistance with the studies contributing to the QIMR and OXGENE collections. The QIMR Study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927,389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, and 552498), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne), and donations from Neville and Shirley Hawkins. Genotyping of the OXGENE and QIMR cases was supported by a grant from the Wellcome Trust (WT084766/Z/08/Z) and makes use of WTCCC2 control data generated by the Wellcome Trust Case Control Consortium (full list of investigators at www.wtccc.org. uk). Funding for the WTCCC project was provided by the Wellcome Trust under award 076113 and 085475. For the endometrial cancer studies, ANECS recruitment was supported by project grants from the NHMRC (339435), Cancer Council Queensland (4196615), and Cancer Council Tasmania (403031 and 457636). 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 control dataset (HCS). SEARCH recruitment was funded by a program grant from Cancer Research UK (C490/A10124). Stage 1 and stage 2 case genotyping was supported by the NHMRC (552402 and 1031333). Control data were generated by the WTCCC, and we acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by UK Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02; funding for this project was provided by the Wellcome Trust under award 085475. NSECG case recruitment was supported by the European Union’s Framework Programme 7 CHIBCHA grant and Wellcome Trust Centre for Human Genetics Core Grant 090532/Z/09Z, and control (CORGI) recruitment by Cancer Research UK. The iCOGS endometrial cancer analysis was supported by an NHMRC project grant (1031333). Funding for iCOGS infrastructure came from the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/ A15007, C5047/A10692, and C8197/A16565), the US National Institutes of Health (R01 CA128978, U19 CA148537, U19 CA148065, and U19 CA148112), the US Department of Defense (W81XWH-10-1-0341), and the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Susan G. Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. 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 the US Public Health Service (R01 CA122443, P30 CA15083, and P50 CA136393), 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, the 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, and Jennie Thomas and the Hunter Medical Research Institute. RENDOCAS was supported through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet (20110222, 20110483, 20110141, and DF 07015), Swedish Labor Market Insurance (100069), and the Swedish Cancer Society (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. For the iCOG controls, BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/A12014). 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. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. The AOCS gratefully acknowledge the cooperation of the participating institutions in Australia and also acknowledge the contribution of the study nurses, research assistants, and all clinical and scientific collaborators. A complete list of the AOCS Study Group can be found at www.aocstudy.org. AOCS was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Foundation of Western Australia, The Cancer Council Tasmania, and the National Health and Medical Research Council of Australia (NHMRC; ID400413, ID400281). The AOCS gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation. ABS and JLH are supported by NHMRC Senior Research Fellowships. TOM is supported by an NHMRC Early Career Fellowship. GWM is supported by an NHMRC Principal Research Fellowship. APM is supported by a Wellcome Senior Fellowship in Basic Biomedical Science. SM is supported by an Australian Research Council Fellowship. The Cox research group is supported by the Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now. Funding Information: We acknowledge with appreciation all women who participated in the QIMR Berghofer Medical Research Institute and OXGENE endometriosis studies and the ANECS-SEARCH, NSECG, and iCOGS endometrial cancer studies. For the endometriosis study, we thank Endometriosis Associations for supporting study recruitment, and the many hospital directors and staff, gynecologists, general practitioners, and pathology services in Australia and the UK who provided assistance with blood collection and confirming diagnoses. We are grateful to the many research assistants and interviewers for assistance with the studies contributing to the QIMR and OXGENE collections. The QIMR Study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927,389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, and 552498), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne), and donations from Neville and Shirley Hawkins. Genotyping of the OXGENE and QIMR cases was supported by a grant from the Wellcome Trust (WT084766/Z/08/Z) and makes use of WTCCC2 control data generated by the Wellcome Trust Case Control Consortium (full list of investigators at www.wtccc.org.uk). Funding for the WTCCC project was provided by the Wellcome Trust under award 076113 and 085475. For the endometrial cancer studies, ANECS recruitment was supported by project grants from the NHMRC (339435), Cancer Council Queensland (4196615), and Cancer Council Tasmania (403031 and 457636). 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 control dataset (HCS). SEARCH recruitment was funded by a program grant from Cancer Research UK (C490/A10124). Stage 1 and stage 2 case genotyping was supported by the NHMRC (552402 and 1031333). Control data were generated by the WTCCC, and we acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by UK Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02; funding for this project was provided by the Wellcome Trust under award 085475. NSECG case recruitment was supported by the European Union's Framework Programme 7 CHIBCHA grant and Wellcome Trust Centre for Human Genetics Core Grant 090532/Z/09Z, and control (CORGI) recruitment by Cancer Research UK. The iCOGS endometrial cancer analysis was supported by an NHMRC project grant (1031333). Funding for iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the US National Institutes of Health (R01 CA128978, U19 CA148537, U19 CA148065, and U19 CA148112), the US Department of Defense (W81XWH-10-1-0341), and the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Susan G. Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. 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 the US Public Health Service (R01 CA122443, P30 CA15083, and P50 CA136393), 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, the 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, and Jennie Thomas and the Hunter Medical Research Institute. RENDOCAS was supported through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet (20110222, 20110483, 20110141, and DF 07015), Swedish Labor Market Insurance (100069), and the Swedish Cancer Society (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. For the iCOG controls, BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/A12014). 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. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. The AOCS gratefully acknowledge the cooperation of the participating institutions in Australia and also acknowledge the contribution of the study nurses, research assistants, and all clinical and scientific collaborators. A complete list of the AOCS Study Group can be found at www.aocstudy.org. AOCS was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Foundation of Western Australia, The Cancer Council Tasmania, and the National Health and Medical Research Council of Australia (NHMRC; ID400413, ID400281). The AOCS gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation. ABS and JLH are supported by NHMRC Senior Research Fellowships. TOM is supported by an NHMRC Early Career Fellowship. GWM is supported by an NHMRC Principal Research Fellowship. APM is supported by a Wellcome Senior Fellowship in Basic Biomedical Science. SM is supported by an Australian Research Council Fellowship. The Cox research group is supported by the Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now. Publisher Copyright: © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
PY - 2018/5
Y1 - 2018/5
N2 - Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (r g = 0.23, P = 9.3 × 10 −3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10 −3 ) and concordance in effect direction (P = 2.0 × 10 −3 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10 −5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10 −8 , OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.
AB - Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (r g = 0.23, P = 9.3 × 10 −3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10 −3 ) and concordance in effect direction (P = 2.0 × 10 −3 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10 −5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10 −8 , OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.
KW - Cross-disease analysis
KW - endometrial cancer
KW - endometriosis
KW - genetic correlation
KW - genome-wide association study
UR - http://www.scopus.com/inward/record.url?scp=85044738188&partnerID=8YFLogxK
U2 - 10.1002/cam4.1445
DO - 10.1002/cam4.1445
M3 - Article
C2 - 29608257
AN - SCOPUS:85044738188
SN - 2045-7634
VL - 7
SP - 1978
EP - 1987
JO - Cancer Medicine
JF - Cancer Medicine
IS - 5
ER -