Cancer Medicine (May 2018)
Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses
- Jodie N. Painter,
- Tracy A. O'Mara,
- Andrew P. Morris,
- Timothy H. T. Cheng,
- Maggie Gorman,
- Lynn Martin,
- Shirley Hodson,
- Angela Jones,
- Nicholas G. Martin,
- Scott Gordon,
- Anjali K. Henders,
- John Attia,
- Mark McEvoy,
- Elizabeth G. Holliday,
- Rodney J. Scott,
- Penelope M. Webb,
- Peter A. Fasching,
- Matthias W. Beckmann,
- Arif B. Ekici,
- Alexander Hein,
- Matthias Rübner,
- Per Hall,
- Kamila Czene,
- Thilo Dörk,
- Matthias Dürst,
- Peter Hillemanns,
- Ingo Runnebaum,
- Diether Lambrechts,
- Frederic Amant,
- Daniela Annibali,
- Jeroen Depreeuw,
- Adriaan Vanderstichele,
- Ellen L. Goode,
- Julie M. Cunningham,
- Sean C. Dowdy,
- Stacey J. Winham,
- Jone Trovik,
- Erling Hoivik,
- Henrica M. J. Werner,
- Camilla Krakstad,
- Katie Ashton,
- Geoffrey Otton,
- Tony Proietto,
- Emma Tham,
- Miriam Mints,
- Shahana Ahmed,
- Catherine S. Healey,
- Mitul Shah,
- Paul D. P. Pharoah,
- Alison M. Dunning,
- Joe Dennis,
- Manjeet K. Bolla,
- Kyriaki Michailidou,
- Qin Wang,
- Jonathan P. Tyrer,
- John L. Hopper,
- Julian Peto,
- Anthony J. Swerdlow,
- Barbara Burwinkel,
- Hermann Brenner,
- Alfons Meindl,
- Hiltrud Brauch,
- Annika Lindblom,
- Jenny Chang‐Claude,
- Fergus J. Couch,
- Graham G. Giles,
- Vessela N. Kristensen,
- Angela Cox,
- Krina T. Zondervan,
- Dale R. Nyholt,
- Stuart MacGregor,
- Grant W. Montgomery,
- Ian Tomlinson,
- Douglas F. Easton,
- Deborah J. Thompson,
- Amanda B. Spurdle
Affiliations
- Jodie N. Painter
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
- Tracy A. O'Mara
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
- Andrew P. Morris
- Wellcome Trust for Human Genetics University of Oxford Oxford UK
- Timothy H. T. Cheng
- Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre University of Oxford Oxford UK
- Maggie Gorman
- Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre University of Oxford Oxford UK
- Lynn Martin
- Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre University of Oxford Oxford UK
- Shirley Hodson
- Department of Clinical Genetics St George's, University of London London UK
- Angela Jones
- Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre University of Oxford Oxford UK
- Nicholas G. Martin
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
- Scott Gordon
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
- Anjali K. Henders
- Institute for Molecular Bioscience University of Queensland Brisbane Queensland Australia
- John Attia
- Hunter Medical Research Institute John Hunter Hospital Newcastle New South Wales Australia
- Mark McEvoy
- Centre for Clinical Epidemiology and Biostatistics School of Medicine and Public Health University of Newcastle Callaghan New South Wales Australia
- Elizabeth G. Holliday
- Hunter Medical Research Institute John Hunter Hospital Newcastle New South Wales Australia
- Rodney J. Scott
- Division of Molecular Medicine Pathology North, John Hunter Hospital Newcastle New South Wales Australia
- Penelope M. Webb
- QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
- Peter A. Fasching
- Department of Gynaecology and Obstetrics University Hospital Erlangen Comprehensive Cancer Center Erlangen‐EMN Friedrich‐Alexander University Erlangen‐Nuremberg Erlangen Germany
- Matthias W. Beckmann
- Department of Gynaecology and Obstetrics University Hospital Erlangen Comprehensive Cancer Center Erlangen‐EMN Friedrich‐Alexander University Erlangen‐Nuremberg Erlangen Germany
- Arif B. Ekici
- Institute of Human Genetics University Hospital Erlangen Comprehensive Cancer Center Erlangen‐EMN Friedrich‐Alexander University Erlangen‐Nuremberg Erlangen Germany
- Alexander Hein
- Department of Gynaecology and Obstetrics University Hospital Erlangen Comprehensive Cancer Center Erlangen‐EMN Friedrich‐Alexander University Erlangen‐Nuremberg Erlangen Germany
- Matthias Rübner
- Department of Gynaecology and Obstetrics University Hospital Erlangen Comprehensive Cancer Center Erlangen‐EMN Friedrich‐Alexander University Erlangen‐Nuremberg Erlangen Germany
- Per Hall
- Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
- Kamila Czene
- Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
- Thilo Dörk
- Gynaecology Research Unit Hannover Medical School Hannover Germany
- Matthias Dürst
- Department of Gynaecology Jena University Hospital ‐ Friedrich Schiller University Jena Germany
- Peter Hillemanns
- Gynaecology Research Unit Hannover Medical School Hannover Germany
- Ingo Runnebaum
- Department of Gynaecology Jena University Hospital ‐ Friedrich Schiller University Jena Germany
- Diether Lambrechts
- VIB Center for Cancer Biology, VIB Leuven Belgium
- Frederic Amant
- Department of Obstetrics and Gynecology Division of Gynecologic Oncology University Hospitals KU Leuven University of Leuven Leuven Belgium
- Daniela Annibali
- Department of Obstetrics and Gynecology Division of Gynecologic Oncology University Hospitals KU Leuven University of Leuven Leuven Belgium
- Jeroen Depreeuw
- Laboratory for Translational Genetics Department of Human Genetics University of Leuven Leuven Belgium
- Adriaan Vanderstichele
- Department of Obstetrics and Gynecology Division of Gynecologic Oncology University Hospitals KU Leuven University of Leuven Leuven Belgium
- Ellen L. Goode
- Department of Health Sciences Research Mayo Clinic Rochester Minnesota
- Julie M. Cunningham
- Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota
- Sean C. Dowdy
- Department of Obstetrics and Gynecology Division of Gynecologic Oncology Mayo Clinic Rochester Minnesota
- Stacey J. Winham
- Department of Health Sciences Research Mayo Clinic Rochester Minnesota
- Jone Trovik
- Centre for Cancerbiomarkers Department of Clinical Science University of Bergen Bergen Norway
- Erling Hoivik
- Centre for Cancerbiomarkers Department of Clinical Science University of Bergen Bergen Norway
- Henrica M. J. Werner
- Centre for Cancerbiomarkers Department of Clinical Science University of Bergen Bergen Norway
- Camilla Krakstad
- Centre for Cancerbiomarkers Department of Clinical Science University of Bergen Bergen Norway
- Katie Ashton
- Hunter Medical Research Institute John Hunter Hospital Newcastle New South Wales Australia
- Geoffrey Otton
- School of Medicine and Public Health University of Newcastle Callaghan New South Wales Australia
- Tony Proietto
- School of Medicine and Public Health University of Newcastle Callaghan New South Wales Australia
- Emma Tham
- Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden
- Miriam Mints
- Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- Shahana Ahmed
- Department of Oncology Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Catherine S. Healey
- Department of Oncology Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Mitul Shah
- Department of Oncology Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Paul D. P. Pharoah
- Department of Oncology Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Alison M. Dunning
- Department of Oncology Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Joe Dennis
- Department of Public Health and Primary Care Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Manjeet K. Bolla
- Department of Public Health and Primary Care Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Kyriaki Michailidou
- Department of Public Health and Primary Care Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Qin Wang
- Department of Public Health and Primary Care Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Jonathan P. Tyrer
- Department of Oncology Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- John L. Hopper
- Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia
- Julian Peto
- Department of Non‐Communicable Disease Epidemiology London School of Hygiene and Tropical Medicine London UK
- Anthony J. Swerdlow
- Division of Genetics and Epidemiology The Institute of Cancer Research London UK
- Barbara Burwinkel
- Department of Obstetrics and Gynecology University of Heidelberg Heidelberg Germany
- Hermann Brenner
- Division of Clinical Epidemiology and Aging Research German Cancer Research Center (DKFZ) Heidelberg Germany
- Alfons Meindl
- Division of Gynaecology and Obstetrics Technische Universität München Munich Germany
- Hiltrud Brauch
- German Cancer Consortium (DKTK) German Cancer Research Center (DKFZ) Heidelberg Germany
- Annika Lindblom
- Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden
- Jenny Chang‐Claude
- Division of Cancer Epidemiology German Cancer Research Center (DKFZ) Heidelberg Germany
- Fergus J. Couch
- Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota
- Graham G. Giles
- Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia
- Vessela N. Kristensen
- Department of Cancer Genetics Institute for Cancer Research Oslo University Hospital Radiumhospitalet Oslo Norway
- Angela Cox
- Department of Oncology and Metabolism Sheffield Institute for Nucleic Acids (SInFoNiA) University of Sheffield Sheffield UK
- Krina T. Zondervan
- Department of Obstetrics & Gynaecology Endometriosis CaRe Centre, Nuffield University of Oxford Oxford UK
- Dale R. Nyholt
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
- Stuart MacGregor
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
- Grant W. Montgomery
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
- Ian Tomlinson
- Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre University of Oxford Oxford UK
- Douglas F. Easton
- Department of Oncology Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Deborah J. Thompson
- Department of Public Health and Primary Care Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Amanda B. Spurdle
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
- DOI
- https://doi.org/10.1002/cam4.1445
- Journal volume & issue
-
Vol. 7,
no. 5
pp. 1978 – 1987
Abstract
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 (rg = 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.
Keywords
- Cross‐disease analysis
- endometrial cancer
- endometriosis
- genome‐wide association study
- genetic correlation
