. 2019 May 1;144(9):2192-2205.

doi: 10.1002/ijc.32029. Epub 2019 Jan 20.

A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants

Sehee Kim¹, Miao Wang¹, Jonathan P Tyrer², Allan Jensen³, Ashley Wiensch⁴, Gang Liu⁵, Alice W Lee⁶, Roberta B Ness⁷, Maxwell Salvatore^{1

4}, Shelley S Tworoger^{8

9}, Alice S Whittemore^{10

11}, Hoda Anton-Culver¹², Weiva Sieh¹³, Sara H Olson¹⁴, Andrew Berchuck¹⁵, Ellen L Goode¹⁶, Marc T Goodman^{17

18}, Jennifer Anne Doherty¹⁹, Georgia Chenevix-Trench²⁰, Mary Anne Rossing^{21

22}, Penelope M Webb²³, Graham G Giles^{24

25

26}, Kathryn L Terry^{9

27}, Argyrios Ziogas¹², Renée T Fortner²⁸, Usha Menon²⁹, Simon A Gayther^{30

31

32}, Anna H Wu³⁰, Honglin Song², Angela Brooks-Wilson^{33

34}, Elisa V Bandera³⁵, Linda S Cook^{36

37}, Daniel W Cramer^{9

27}, Roger L Milne^{24

25

38}, Stacey J Winham¹⁶, Susanne K Kjaer^{3

39}, Francesmary Modugno^{40

41

42}, Pamela J Thompson¹⁷, Jenny Chang-Claude^{28

43}, Holly R Harris²¹, Joellen M Schildkraut⁴⁴, Nhu D Le⁴⁵, Nico Wentzensen⁴⁶, Britton Trabert⁴⁶, Estrid Høgdall^{3

47}, David Huntsman^{48

49}, Malcolm C Pike^{14

50}, Paul D P Pharoah^{2

51}, Celeste Leigh Pearce^{4

31}, Bhramar Mukherjee¹

Affiliations

¹ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
³ Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
⁴ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁵ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶ Department of Public Health, California State University, Fullerton, Fullerton, CA, USA.
⁷ University of Texas School of Public Health, Houston, TX, USA.
⁸ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
⁹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁰ Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹² Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
¹³ Department of Genetics and Genomic Sciences, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
¹⁵ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
¹⁶ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
¹⁷ Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁸ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Community and Population Health Research Institute, Los Angeles, CA, USA.
¹⁹ Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
²⁰ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
²¹ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²² Department of Epidemiology, University of Washington, Seattle, WA, USA.
²³ Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
²⁴ Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia.
²⁵ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
²⁶ Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
²⁷ Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.
²⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁹ Gynaecological Cancer Research Centre, Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.
³⁰ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³¹ Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³² Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³³ Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
³⁴ Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
³⁵ Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
³⁶ University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
³⁷ Division of Cancer Care, Department of Population Health Research, Alberta Health Services, Calgary, AB, Canada.
³⁸ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
³⁹ Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁴⁰ Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
⁴¹ Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
⁴² Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴³ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁴ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
⁴⁵ Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
⁴⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁴⁷ Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
⁴⁸ British Columbia's Ovarian Cancer Research (OVCARE) program, Vancouver General Hospital, BC Cancer and University of British Columbia.
⁴⁹ Department of Pathology and Laboratory Medicine, and Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
⁵⁰ Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
⁵¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.

PMID: 30499236
PMCID: PMC6399057
DOI: 10.1002/ijc.32029

A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants

Sehee Kim et al. Int J Cancer. 2019.

. 2019 May 1;144(9):2192-2205.

doi: 10.1002/ijc.32029. Epub 2019 Jan 20.

Authors

Affiliations

¹ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
³ Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
⁴ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁵ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶ Department of Public Health, California State University, Fullerton, Fullerton, CA, USA.
⁷ University of Texas School of Public Health, Houston, TX, USA.
⁸ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
⁹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁰ Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹² Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
¹³ Department of Genetics and Genomic Sciences, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
¹⁵ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
¹⁶ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
¹⁷ Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁸ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Community and Population Health Research Institute, Los Angeles, CA, USA.
¹⁹ Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
²⁰ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
²¹ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²² Department of Epidemiology, University of Washington, Seattle, WA, USA.
²³ Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
²⁴ Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia.
²⁵ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
²⁶ Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
²⁷ Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.
²⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁹ Gynaecological Cancer Research Centre, Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.
³⁰ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³¹ Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³² Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³³ Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
³⁴ Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
³⁵ Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
³⁶ University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
³⁷ Division of Cancer Care, Department of Population Health Research, Alberta Health Services, Calgary, AB, Canada.
³⁸ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
³⁹ Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁴⁰ Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
⁴¹ Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
⁴² Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴³ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁴ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
⁴⁵ Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
⁴⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁴⁷ Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
⁴⁸ British Columbia's Ovarian Cancer Research (OVCARE) program, Vancouver General Hospital, BC Cancer and University of British Columbia.
⁴⁹ Department of Pathology and Laboratory Medicine, and Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
⁵⁰ Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
⁵¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.

PMID: 30499236
PMCID: PMC6399057
DOI: 10.1002/ijc.32029

Abstract

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10^-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.

Keywords: G × E; additive interaction; genetics; ovarian cancer.

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Figures

**Figure 1A–1C.**
ORs of oral contraceptive (OCP) use, marginally, or stratified by number of risk allele of rs13255292. The ORs were calculated from a logistic regression model assuming log-additive effect of SNPs. (A) OR of OCP (ever vs never) (B) OR of 1 to 5 years of OCP use (vs < 1 year) (B) OR of more than 5 years of OCP use (vs < 1 year).

**Figure 2A–2C.**
Estimated absolute risk (AR) of ovarian cancer given OCP use and number of copies of C allele, among non-Hispanic white college graduates aged below 50 with no family history of ovarian cancer, BMI below 25, no tubal ligation, no endometriosis, with one child. The ARs were calculated from a logistic regression model assuming log-additive effect of SNPs while all covariates fixed at their most frequent level as described above. (A) ARs stratified by OCP (ever vs never) and genotype (B) ARs stratified by 1 to 5 years of OCP use (vs < 1 year) and genotype (F) ARs stratified by more than 5 years of OCP use (vs < 1 year) and genotype. Risk differences were also reported as the solid black bar.

See this image and copyright information in PMC

References

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A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants

Affiliations

A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials