CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk

Xabier Garcia-Albeniz^{1

2}, Anja Rudolph³, Carolyn Hutter⁴, Emily White^{5

6}, Yi Lin^{5

6}, Stephanie A Rosse^{5

6}, Jane C Figueiredo⁷, Tabitha A Harrison^{5

6}, Shuo Jiao^{5

6}, Hermann Brenner^{8

9

10}, Graham Casey⁷, Thomas J Hudson¹¹, Mark Thornquist^{5

6}, Loic Le Marchand¹², John Potter^{5

6}, Martha L Slattery¹³, Brent Zanke¹⁴, John A Baron¹⁵, Bette J Caan¹⁶, Stephen J Chanock¹⁷, Sonja I Berndt¹⁷, Deanna Stelling^{5

6}, Charles S Fuchs^{18

19

20}, Michael Hoffmeister⁸, Katja Butterbach⁸, Mengmeng Du^{5

6}, W James Gauderman²¹, Marc J Gunter²², Mathieu Lemire¹¹, Shuji Ogino^{18

19

20}, Jennifer Lin², Richard B Hayes²³, Robert W Haile²⁴, Robert E Schoen²⁵, Greg S Warnick^{5

6}, Mark A Jenkins²⁶, Stephen N Thibodeau²⁷, Fredrick R Schumacher⁷, Noralane M Lindor²⁸, Laurence N Kolonel¹², John L Hopper²⁶, Jian Gong^{5

6}, Daniela Seminara⁴, Bethann M Pflugeisen²⁹, Cornelia M Ulrich^{5

9

30}, Conghui Qu²⁹, David Duggan³¹, Michelle Cotterchio³², Peter T Campbell³³, Christopher S Carlson^{5

6}, Polly A Newcomb^{5

6}, Edward Giovannucci^{1

2}, Li Hsu^{5

6}, Andrew T Chan^{2

34}, Ulrike Peters^{5

6}, Jenny Chang-Claude^{3

35}

Affiliations

¹ Department of Epidemiology, Harvard T.H., Chan School of Public Health, Boston, MA 02115, USA.
² Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
³ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁴ Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
⁶ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017, USA.
⁷ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁸ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁹ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹⁰ German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
¹¹ Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
¹² Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
¹³ Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
¹⁴ Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
¹⁵ Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7080, USA.
¹⁶ Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA 94612, USA.
¹⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4608, USA.
¹⁸ Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
¹⁹ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
²⁰ Department of Epidemiology, Harvard T.H., Chan School of Public Health, Boston, MA 02215, USA.
²¹ Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
²² Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, UK.
²³ Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY 10016, USA.
²⁴ Department of Medicine, Stanford University, Stanford, CA 94304, USA.
²⁵ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2582, USA.
²⁶ Melbourne School of Population Health, The University of Melbourne, Melbourne, VIC 3010, Australia.
²⁷ Departments of Laboratory Medicine, Pathology and Laboratory Genetics, Mayo Clinic, Scottsdale, AZ 85259, USA.
²⁸ Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ 85259, USA.
²⁹ Department of Cancer Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
³⁰ Department of Population Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
³¹ Translational Genomics Research Institute (Tgen), Phoenix, AZ 85004, USA.
³² Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON M5G 2L7, Canada.
³³ Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA.
³⁴ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
³⁵ University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

PMID: 26766742
PMCID: PMC4815813
DOI: 10.1038/bjc.2015.443

Meta-Analysis

CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk

Xabier Garcia-Albeniz et al. Br J Cancer. 2016.

. 2016 Jan 19;114(2):221-9.

doi: 10.1038/bjc.2015.443. Epub 2016 Jan 14.

Authors

Affiliations

¹ Department of Epidemiology, Harvard T.H., Chan School of Public Health, Boston, MA 02115, USA.
² Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
³ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁴ Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
⁶ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017, USA.
⁷ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁸ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁹ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹⁰ German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
¹¹ Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
¹² Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
¹³ Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
¹⁴ Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
¹⁵ Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7080, USA.
¹⁶ Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA 94612, USA.
¹⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4608, USA.
¹⁸ Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
¹⁹ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
²⁰ Department of Epidemiology, Harvard T.H., Chan School of Public Health, Boston, MA 02215, USA.
²¹ Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
²² Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, UK.
²³ Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY 10016, USA.
²⁴ Department of Medicine, Stanford University, Stanford, CA 94304, USA.
²⁵ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2582, USA.
²⁶ Melbourne School of Population Health, The University of Melbourne, Melbourne, VIC 3010, Australia.
²⁷ Departments of Laboratory Medicine, Pathology and Laboratory Genetics, Mayo Clinic, Scottsdale, AZ 85259, USA.
²⁸ Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ 85259, USA.
²⁹ Department of Cancer Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
³⁰ Department of Population Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
³¹ Translational Genomics Research Institute (Tgen), Phoenix, AZ 85004, USA.
³² Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON M5G 2L7, Canada.
³³ Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA.
³⁴ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
³⁵ University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

PMID: 26766742
PMCID: PMC4815813
DOI: 10.1038/bjc.2015.443

Abstract

Background: Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT.

Methods: We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test.

Results: The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 × 10(-9)). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 × 10(-5) (alpha threshold=3.1 × 10(-4)). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively.

Conclusions: Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.

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Figures

**Figure 1**
Forest plot for meta-analysis of the interaction between SNP and oestrogen plus progestogen use, using the empirical Bayes (A and C) and case–control logistic regression method (B and D) for rs964293 (A and B) and rs6023015 (C and D). DALS and PLCO studies are not plotted because they do not have information on the type of hormone compound.

**Figure 2**
Forest plot for meta-analysis of the marginal association of oestrogen plus progestogen with colorectal cancer risk in strata defined by zero, one or two minor alleles of rs964293 (A, B and C, respectively) and rs6023015 (D, E and F, respectively).

See this image and copyright information in PMC

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CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk

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CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk

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