A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes

Sally Mortlock; Rosario I Corona; Pik Fang Kho; Paul Pharoah; Ji-Heui Seo; Matthew L Freedman; Simon A Gayther; Matthew T Siedhoff; Peter A W Rogers; Ronald Leuchter; Christine S Walsh; Ilana Cass; Beth Y Karlan; B J Rimel; Ovarian Cancer Association Consortium, International Endometriosis Genetics Consortium; Grant W Montgomery; Kate Lawrenson; Siddhartha P Kar

doi:10.1016/j.xcrm.2022.100542

A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes

Cell Rep Med. 2022 Mar 15;3(3):100542. doi: 10.1016/j.xcrm.2022.100542.

Authors

Sally Mortlock¹, Rosario I Corona², Pik Fang Kho^{3

4}, Paul Pharoah^{5

6}, Ji-Heui Seo⁷, Matthew L Freedman^{7

8}, Simon A Gayther⁹, Matthew T Siedhoff¹⁰, Peter A W Rogers¹¹, Ronald Leuchter¹², Christine S Walsh¹³, Ilana Cass¹², Beth Y Karlan¹⁴, B J Rimel¹²; Ovarian Cancer Association Consortium, International Endometriosis Genetics Consortium; Grant W Montgomery¹, Kate Lawrenson^{2

9

12}, Siddhartha P Kar^{15

16}

Affiliations

¹ The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
² Women's Cancer Research Program at Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁴ School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
⁵ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN Cambridge, UK.
⁶ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, CB1 8RN Cambridge, UK.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
⁹ Center for Bioinformatics and Functional Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁰ Division of Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹¹ University of Melbourne Department of Obstetrics and Gynaecology, and Gynaecology Research Centre, Royal Women's Hospital, Parkville, VIC 3052, Australia.
¹² Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹³ Department of Obstetrics and Gynecology, University of Colorado, Aurora, CO, USA.
¹⁴ Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
¹⁵ Medical Research Council Integrative Epidemiology Unit, University of Bristol, BS8 2BN Bristol, UK.
¹⁶ Population Health Sciences, Bristol Medical School, University of Bristol, BS8 2BN Bristol, UK.

Abstract

Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Using data from large endometriosis and EOC genome-wide association meta-analyses, we estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. We estimate a significant genetic correlation (r_g) between endometriosis and clear cell (r_g = 0.71), endometrioid (r_g = 0.48), and high-grade serous (r_g = 0.19) ovarian cancer, associations supported by Mendelian randomization analyses. Bivariate meta-analysis identified 28 loci associated with both endometriosis and EOC, including 19 with evidence for a shared underlying association signal. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlights several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.

Keywords: Mendelian randomization; endometriosis; epithelial ovarian cancer; genetic association; genetic correlation; genetic risk; histotype; meta-analysis.

Publication types

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

MeSH terms

Carcinoma, Ovarian Epithelial / genetics
Endometriosis* / genetics
Female
Genome-Wide Association Study
Humans
Neoplasms, Glandular and Epithelial* / complications
Ovarian Neoplasms* / genetics

Abstract

Publication types

MeSH terms

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