Patterns of Associations with Epidemiologic Factors by High-Grade Serous Ovarian Cancer Gene Expression Subtypes

Lindsay J Collin¹, Kara L Cushing-Haugen², Kathryn L Terry^{3

4}, Ellen L Goode⁵, Anna H Wu⁶, Holly R Harris^{2

7}, Naoko Sasamoto³, Daniel W Cramer^{3

4}, Francesmary Modugno^{8

9

10}, Esther Elishaev^{8

9

10}, Zhuxuan Fu¹¹, Kirsten B Moysich¹², Peter A Fasching¹³, Celeste Leigh Pearce¹⁴, Usha Menon¹⁵, Aleksandra Gentry-Maharaj^{16

17}, Simon A Gayther¹⁷, Nicolas Wentzensen¹⁸, Marc T Goodman^{19

20}, Joshy George²¹, Aline Talhouk²², Michael S Anglesio²², Susan J Ramus^{23

24}, David D L Bowtell^{25

26}, Shelley S Tworoger^{27

28}, Joellen M Schildkraut²⁹, Penelope M Webb^{30

31}, Jennifer A Doherty¹

Affiliations

¹ Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
² Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington.
³ Department of Obstetrics and Gynecology, Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
⁴ Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
⁵ Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota.
⁶ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California.
⁷ Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington.
⁸ Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania.
⁹ Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
¹⁰ Women's Cancer Research Center, Magee-Women's Research Institute and Hillman Cancer Center, Pittsburgh, Pennsylvania.
¹¹ University of Missouri's Healthcare Institute for Innovations in Quality and Saint Luke's Mid America Heart Institute, Kansas City, Missouri.
¹² Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
¹³ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
¹⁴ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan.
¹⁵ MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom.
¹⁶ Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom.
¹⁷ Center for Bioinformatics and Functional Genomics and the Cedars-Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, California.
¹⁸ Clinical Epidemiology Unit, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
¹⁹ Cancer Prevention and Control Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
²⁰ Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
²¹ The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
²² Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada.
²³ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, Australia.
²⁴ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW, Sydney, Australia.
²⁵ Peter MacCallum Cancer Centre, Victoria, Australia.
²⁶ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
²⁷ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
²⁸ Division of Oncological Sciences, School of Medicine, Oregon Health & Science University, Portland, Oregon.
²⁹ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
³⁰ Gynecological Cancers Group, Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
³¹ University of Queensland, School of Public Health, Brisbane, Australia.

PMID: 40009771
PMCID: PMC12046315
DOI: 10.1158/1055-9965.EPI-24-1143

Patterns of Associations with Epidemiologic Factors by High-Grade Serous Ovarian Cancer Gene Expression Subtypes

Lindsay J Collin et al. Cancer Epidemiol Biomarkers Prev. 2025.

. 2025 May 2;34(5):762-773.

doi: 10.1158/1055-9965.EPI-24-1143.

Authors

Affiliations

¹ Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
² Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington.
³ Department of Obstetrics and Gynecology, Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
⁴ Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
⁵ Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota.
⁶ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California.
⁷ Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington.
⁸ Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania.
⁹ Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
¹⁰ Women's Cancer Research Center, Magee-Women's Research Institute and Hillman Cancer Center, Pittsburgh, Pennsylvania.
¹¹ University of Missouri's Healthcare Institute for Innovations in Quality and Saint Luke's Mid America Heart Institute, Kansas City, Missouri.
¹² Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
¹³ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
¹⁴ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan.
¹⁵ MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom.
¹⁶ Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom.
¹⁷ Center for Bioinformatics and Functional Genomics and the Cedars-Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, California.
¹⁸ Clinical Epidemiology Unit, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
¹⁹ Cancer Prevention and Control Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
²⁰ Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
²¹ The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
²² Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada.
²³ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, Australia.
²⁴ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW, Sydney, Australia.
²⁵ Peter MacCallum Cancer Centre, Victoria, Australia.
²⁶ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
²⁷ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
²⁸ Division of Oncological Sciences, School of Medicine, Oregon Health & Science University, Portland, Oregon.
²⁹ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
³⁰ Gynecological Cancers Group, Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
³¹ University of Queensland, School of Public Health, Brisbane, Australia.

PMID: 40009771
PMCID: PMC12046315
DOI: 10.1158/1055-9965.EPI-24-1143

Abstract

Background: Ovarian high-grade serous carcinomas (HGSC) comprise four distinct molecular subtypes based on mRNA expression patterns, with differential survival. Understanding risk factor associations is important to elucidate the etiology of HGSC. We investigated associations between different epidemiologic risk factors and HGSC molecular subtypes.

Methods: We pooled data from 11 case-control studies with epidemiologic and tumor gene expression data from custom NanoString CodeSets developed through a collaboration within the Ovarian Tumor Tissue Analysis consortium. The PrOTYPE-validated NanoString-based 55-gene classifier was used to assign HGSC gene expression subtypes. We examined associations between epidemiologic factors and HGSC subtypes in 2,070 cases and 16,633 controls using multivariable-adjusted polytomous regression models.

Results: Among the 2,070 HGSC cases, 556 (27%) were classified as C1.MES, 340 (16%) as C5.PRO, 538 (26%) as C2.IMM, and 636 (31%) as C4.DIF. The key factors, including oral contraceptive use, parity, breastfeeding, and family history of ovarian cancer, were similarly associated with all subtypes. Heterogeneity was observed for several factors. Former smoking [OR = 1.25; 95% confidence interval (CI) = 1.03, 1.51] and genital powder use (OR = 1.42; 95% CI = 1.08, 1.86) were uniquely associated with C2.IMM. History of endometriosis was associated with C5.PRO (OR = 1.46; 95% CI = 0.98, 2.16) and C4.DIF (OR = 1.27; 95% CI = 0.94, 1.71) only. Family history of breast cancer (OR = 1.44; 95% CI = 1.16, 1.78) and current smoking (OR = 1.40; 95% CI = 1.11, 1.76) were associated with C4.DIF only.

Conclusions: This study observed heterogeneous associations of epidemiologic and modifiable factors with HGSC molecular subtypes.

Impact: The different patterns of associations may provide key information about the etiology of the four subtypes.

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Conflict of interest statement

L.J. Collin reports grants from NCI during the conduct of the study, as well as personal fees from Epidemiologic Research & Methods LLC outside the submitted work. K.L. Terry reports grants from NIH during the conduct of the study. N. Sasamoto reports grants from Department of Defense, Rivkin Foundation, American Cancer Society, Aspira Women’s Health, and NIH outside the submitted work. F. Modugno reports grants from NCI and Department of Defense during the conduct of the study. P.A. Fasching reports grants and personal fees from Novartis and Pfizer, grants from BioNTech, and personal fees from Daiichi Sankyo, AstraZeneca, Eisai, Merck Sharp & Dohme, Cepheid, Eli Lilly and Company, Seagen, Roche, Agendia, Gilead Sciences, Mylan, Menarini Stemline, Veracyte, and Guardant Health outside the submitted work. C.L. Pearce reports grants from NIH and Department of Defense during the conduct of the study. U. Menon reports grants and personal fees from Mercy BioAnalytics, grants from Intelligent Lab on Fiber and RNA Guardian and other support from Synteny outside the submitted work. A. Gentry-Maharaj reports other support from Medical Research Council, Cancer Research UK, NIH Research, and The Eve Appeal during the conduct of the study; other support from Intelligent Lab on Fiber, RNA Guardian, Micronoma, and Mercy BioAnalytics outside the submitted work; research collaborations with academic institutions: University of Cambridge, QIMR Berghofer Medical Research Institute, Imperial College London, University of Innsbruck, and Dana-Farber USA; and being the Cancer Research UK ACED co-director of research domain trials. M.S. Anglesio reports grants from Health Research BC and NIH during the conduct of the study. D.D.L. Bowtell reports grants from Roche-Genentech (paid to institution) and AstraZeneca (paid to institution) and personal fees from Exo Therapeutics and Cartherics outside the submitted work. S.S. Tworoger reports grants from NIH/NCI during the conduct of the study; grants from NIH, state of Florida, Department of Defense, Bristol Myers Squibb, and American Cancer Society and personal fees from American Association for Cancer Research, Ponce Health Sciences University, Ovarian Cancer Research Alliance, University of North Carolina, UNC Lineberger Comprehensive Cancer Center, and Roswell Park Comprehensive Cancer Center outside the submitted work; and nonpaid relationships member of the external advisory committee of the California Teachers Study (City of Hope), The Tomorrow Project (Alberta Cancer Center), and TRANCE program at Fred Hutchinson Cancer Center. J.M. Schildkraut reports grants from NIH/NCI during the conduct of the study. P.M. Webb reports grants from US Army Medical Research and Materiel Command, National Health and Medical Research Council of Australia, cancer councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania, and Cancer Foundation of Western Australia during the conduct of the study. J.A. Doherty reports grants from NIH during the conduct of the study. No disclosures were reported by the other authors.

Figures

**Figure 1.**
Heatmap associating epidemiologic factors with HGSC subtypes among 2,070 cases and 16,633 disease-free controls in the 11 pooled case–control studies. The dichotomized variables included OC use (ever vs. never), number of full-term pregnancies (3+ vs. none), age at last pregnancy (35+ vs. < 25 years), breastfeeding (2+ years vs. never), age at menarche (14+ vs. ≤11 years), E-only hormone therapy (10+ years vs. never), endometriosis (yes vs. no), tubal ligation (yes vs. no), BMI at 18 years of age (≥25 vs. < 25 kg/m²), regular aspirin use (any vs. none), genital powder use (any vs. none), current smoking (vs. never), former smoking (vs. never), alcohol use (ever vs. never), first-degree family history of ovarian cancer (vs. none), and first-degree family history of breast cancer only (vs. none). BrCa, breast cancer; HRT, hormone replacement therapy; Hx, history; OvCa, ovarian cancer.

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References

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Patterns of Associations with Epidemiologic Factors by High-Grade Serous Ovarian Cancer Gene Expression Subtypes

Affiliations

Patterns of Associations with Epidemiologic Factors by High-Grade Serous Ovarian Cancer Gene Expression Subtypes

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous