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

doi:10.1002/cam4.1445

Genetic overlap between endometriosis and endometrial cancer: evidence from cross-disease genetic correlation and GWAS meta-analyses

Cancer Med. 2018 May;7(5):1978-1987. doi: 10.1002/cam4.1445. Epub 2018 Apr 2.

Authors

Jodie N Painter¹, Tracy A O'Mara¹, Andrew P Morris^{2

3}, Timothy H T Cheng⁴, Maggie Gorman⁴, Lynn Martin⁴, Shirley Hodson⁵, Angela Jones⁴, Nicholas G Martin¹, Scott Gordon¹, Anjali K Henders⁶, John Attia^{7

8}, Mark McEvoy⁸, Elizabeth G Holliday^{7

8}, Rodney J Scott^{9

10}, Penelope M Webb¹¹, Peter A Fasching^{12

13}, Matthias W Beckmann¹², Arif B Ekici¹⁴, Alexander Hein¹², Matthias Rübner¹², Per Hall¹⁵, Kamila Czene¹⁵, Thilo Dörk¹⁶, Matthias Dürst¹⁷, Peter Hillemanns¹⁶, Ingo Runnebaum¹⁷, Diether Lambrechts^{18

19}, Frederic Amant²⁰, Daniela Annibali²⁰, Jeroen Depreeuw^{19

20

21}, Adriaan Vanderstichele²⁰, Ellen L Goode²², Julie M Cunningham²³, Sean C Dowdy²⁴, Stacey J Winham²², Jone Trovik^{25

26}, Erling Hoivik^{25

26}, Henrica M J Werner^{25

26}, Camilla Krakstad^{25

26}, Katie Ashton^{7

10

27}, Geoffrey Otton²⁸, Tony Proietto²⁸, Emma Tham^{29

30}, Miriam Mints³¹, Shahana Ahmed³², Catherine S Healey³², Mitul Shah³², Paul D P Pharoah^{32

33}, Alison M Dunning³², Joe Dennis³³, Manjeet K Bolla³³, Kyriaki Michailidou^{33

34}, Qin Wang³³, Jonathan P Tyrer³², John L Hopper³⁵, Julian Peto³⁶, Anthony J Swerdlow^{37

38}, Barbara Burwinkel^{39

40}, Hermann Brenner^{41

42

43}, Alfons Meindl⁴⁴, Hiltrud Brauch^{43

45

46}, Annika Lindblom²⁹, Jenny Chang-Claude^{47

48}, Fergus J Couch²³, Graham G Giles^{35

49}, Vessela N Kristensen^{50

51

52}, Angela Cox⁵³, Krina T Zondervan⁵⁴, Dale R Nyholt^{1

55}, Stuart MacGregor¹, Grant W Montgomery^{1

6}, Ian Tomlinson⁴, Douglas F Easton^{32

33}, Deborah J Thompson³³, Amanda B Spurdle¹

Affiliations

¹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
² Wellcome Trust for Human Genetics, University of Oxford, Oxford, UK.
³ Department of Biostatistics, University of Liverpool, Liverpool, UK.
⁴ Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
⁵ Department of Clinical Genetics, St George's, University of London, London, UK.
⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
⁷ Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁸ Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
⁹ Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, New South Wales, Australia.
¹⁰ Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, New South Wales, Australia.
¹¹ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹² Department of Gynaecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
¹³ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California.
¹⁴ Institute of Human Genetics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
¹⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁶ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
¹⁷ Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany.
¹⁸ VIB Center for Cancer Biology, VIB, Leuven, Belgium.
¹⁹ Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
²⁰ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals KU Leuven, University of Leuven, Leuven, Belgium.
²¹ Vesalius Research Center, VIB, Leuven, Belgium.
²² Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
²³ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
²⁴ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mayo Clinic, Rochester, Minnesota.
²⁵ Centre for Cancerbiomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
²⁶ Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
²⁷ Centre for Information Based Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
²⁸ School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
²⁹ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
³⁰ Clinical Genetics, Karolinska Institutet, Stockholm, Sweden.
³¹ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
³² Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
³³ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
³⁴ Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
³⁵ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
³⁶ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
³⁷ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
³⁸ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
³⁹ Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
⁴⁰ Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴¹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴² Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁴³ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁴ Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
⁴⁵ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
⁴⁶ University of Tübingen, Tübingen, Germany.
⁴⁷ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁸ Research Group Genetic Cancer Epidemiology, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁹ Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁵⁰ Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
⁵¹ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁵² Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
⁵³ Department of Oncology and Metabolism, Sheffield Institute for Nucleic Acids (SInFoNiA), University of Sheffield, Sheffield, UK.
⁵⁴ Department of Obstetrics & Gynaecology, Endometriosis CaRe Centre, Nuffield, University of Oxford, Oxford, UK.
⁵⁵ Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia.

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.

Keywords: Cross-disease analysis; endometrial cancer; endometriosis; genetic correlation; genome-wide association study.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Australia / epidemiology
Endometrial Neoplasms / epidemiology
Endometrial Neoplasms / genetics*
Endometriosis / epidemiology
Endometriosis / genetics*
Endometrium / pathology
Female
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study
Humans
Polymorphism, Single Nucleotide / genetics
Receptor-Like Protein Tyrosine Phosphatases, Class 2 / genetics*
STAT3 Transcription Factor / metabolism

Substances

STAT3 Transcription Factor
STAT3 protein, human
PTPRD protein, human
Receptor-Like Protein Tyrosine Phosphatases, Class 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding