Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk

Yu Tian^{1

2}, Andre E Kim³, Stephanie A Bien⁴, Yi Lin⁴, Conghui Qu⁴, Tabitha A Harrison⁴, Robert Carreras-Torres^{5

6

7}, Virginia Díez-Obrero^{5

6

7}, Niki Dimou⁸, David A Drew^{9

10}, Akihisa Hidaka⁴, Jeroen R Huyghe⁴, Kristina M Jordahl^{4

11}, John Morrison³, Neil Murphy⁸, Mireia Obón-Santacana^{5

6

7}, Cornelia M Ulrich^{12

13}, Jennifer Ose^{12

13}, Anita R Peoples^{12

13}, Edward A Ruiz-Narvaez¹⁴, Anna Shcherbina¹⁵, Mariana C Stern¹⁶, Yu-Ru Su^{4

17}, Franzel J B van Duijnhoven¹⁸, Volker Arndt¹⁹, James W Baurley^{20

21}, Sonja I Berndt²², D Timothy Bishop²³, Hermann Brenner^{19

24

25}, Daniel D Buchanan^{26

27

28}, Andrew T Chan^{9

10

29

30

31

32}, Jane C Figueiredo^{33

34}, Steven Gallinger³⁵, Stephen B Gruber¹⁶, Sophia Harlid³⁶, Michael Hoffmeister¹⁹, Mark A Jenkins³⁷, Amit D Joshi³¹, Temitope O Keku³⁸, Susanna C Larsson³⁹, Loic Le Marchand⁴⁰, Li Li⁴¹, Graham G Giles^{37

42

43}, Roger L Milne^{37

42

43}, Hongmei Nan^{44

45}, Rami Nassir⁴⁶, Shuji Ogino^{30

31

47

48}, Arif Budiarto²⁰, Elizabeth A Platz⁴⁹, John D Potter^{4

50}, Ross L Prentice^{4

51}, Gad Rennert^{52

53

54}, Lori C Sakoda^{4

55}, Robert E Schoen⁵⁶, Martha L Slattery⁵⁷, Stephen N Thibodeau⁵⁸, Bethany Van Guelpen^{36

59}, Kala Visvanathan⁴⁹, Emily White^{4

11}, Alicja Wolk³⁹, Michael O Woods⁶⁰, Anna H Wu³⁴, Peter T Campbell⁶¹, Graham Casey⁶², David V Conti¹⁶, Marc J Gunter⁸, Anshul Kundaje^{63

64}, Juan Pablo Lewinger³, Victor Moreno^{5

6

7

65}, Polly A Newcomb^{4

11}, Bens Pardamean²⁰, Duncan C Thomas¹⁶, Konstantinos K Tsilidis^{66

67}, Ulrike Peters^{4

11}, W James Gauderman¹⁶, Li Hsu^{4

51}, Jenny Chang-Claude^{1

68}

Affiliations

¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² School of Public Health, Capital Medical University, Beijing, China.
³ Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁵ Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
⁶ Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
⁷ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
⁸ Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
⁹ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
¹² Huntsman Cancer Institute, Salt Lake City, UT, USA.
¹³ Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
¹⁴ Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
¹⁵ Biomedical Informatics Program, Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA.
¹⁶ Division of Biostatistics, Department of Population and Public Health Sciences & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁷ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
¹⁸ Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands.
¹⁹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁰ Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
²¹ BioRealm LLC, Walnut, CA, USA.
²² Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
²³ Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
²⁴ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²⁵ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁶ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
²⁷ University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
²⁸ Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
²⁹ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³⁰ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
³² Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
³³ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³⁴ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³⁵ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
³⁶ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
³⁷ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
³⁸ Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
³⁹ Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
⁴⁰ University of Hawaii Cancer Center, Honolulu, HI, USA.
⁴¹ Department of Family Medicine, University of Virginia, Charlottesville, VA, USA.
⁴² Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁴³ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
⁴⁴ Department of Global Health, Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA.
⁴⁵ Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA.
⁴⁶ Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia.
⁴⁷ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴⁸ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴⁹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵⁰ Research Centre for Hauora and Health, Massey University, Wellington, New Zealand.
⁵¹ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁵² Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
⁵³ Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
⁵⁴ Clalit National Cancer Control Center, Haifa, Israel.
⁵⁵ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁵⁶ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁵⁷ Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
⁵⁸ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁵⁹ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
⁶⁰ Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL,Canada.
⁶¹ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
⁶² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁶³ Department of Genetics, Stanford University, Stanford, CA, USA.
⁶⁴ Department of Computer Science, Stanford University, Stanford, CA, USA.
⁶⁵ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
⁶⁶ Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
⁶⁷ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
⁶⁸ University Cancer Centre Hamburg (UCCH), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

PMID: 35512400
PMCID: PMC9360460
DOI: 10.1093/jnci/djac094

Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk

Yu Tian et al. J Natl Cancer Inst. 2022.

. 2022 Aug 8;114(8):1135-1148.

doi: 10.1093/jnci/djac094.

Authors

Affiliations

¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² School of Public Health, Capital Medical University, Beijing, China.
³ Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁵ Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
⁶ Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
⁷ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
⁸ Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
⁹ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
¹² Huntsman Cancer Institute, Salt Lake City, UT, USA.
¹³ Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
¹⁴ Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
¹⁵ Biomedical Informatics Program, Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA.
¹⁶ Division of Biostatistics, Department of Population and Public Health Sciences & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁷ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
¹⁸ Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands.
¹⁹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁰ Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
²¹ BioRealm LLC, Walnut, CA, USA.
²² Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
²³ Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
²⁴ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²⁵ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁶ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
²⁷ University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
²⁸ Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
²⁹ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³⁰ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
³² Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
³³ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³⁴ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³⁵ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
³⁶ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
³⁷ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
³⁸ Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
³⁹ Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
⁴⁰ University of Hawaii Cancer Center, Honolulu, HI, USA.
⁴¹ Department of Family Medicine, University of Virginia, Charlottesville, VA, USA.
⁴² Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁴³ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
⁴⁴ Department of Global Health, Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA.
⁴⁵ Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA.
⁴⁶ Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia.
⁴⁷ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴⁸ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴⁹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵⁰ Research Centre for Hauora and Health, Massey University, Wellington, New Zealand.
⁵¹ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁵² Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
⁵³ Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
⁵⁴ Clalit National Cancer Control Center, Haifa, Israel.
⁵⁵ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁵⁶ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁵⁷ Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
⁵⁸ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁵⁹ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
⁶⁰ Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL,Canada.
⁶¹ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
⁶² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁶³ Department of Genetics, Stanford University, Stanford, CA, USA.
⁶⁴ Department of Computer Science, Stanford University, Stanford, CA, USA.
⁶⁵ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
⁶⁶ Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
⁶⁷ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
⁶⁸ University Cancer Centre Hamburg (UCCH), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

PMID: 35512400
PMCID: PMC9360460
DOI: 10.1093/jnci/djac094

Abstract

Background: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk.

Methods: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants.

Results: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4).

Conclusion: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

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Figures

**Figure 1.**
Association of any menopausal hormone therapy use with the risk of colorectal cancer. CI = confidence interval; OR = odds ratio.

**Figure 2.**
Association of use of estrogen only with the risk of colorectal cancer. CI = confidence interval; OR = odds ratio.

**Figure 3.**
Association of use of combined estrogen-progestogen with the risk of colorectal cancer. CI = confidence interval; OR = odds ratio.

See this image and copyright information in PMC

References

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Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk

Affiliations

Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk

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