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Identification of genetic and lifestyle determinants of estrogen metabolism profiles

Principal Investigator
Name
Fangcheng Yuan
Degrees
Sc.M.
Institution
Vanderbilt University Medical Center
Position Title
Doctoral Student
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
PLCO-1199
Initial CDAS Request Approval
Apr 19, 2023
Title
Identification of genetic and lifestyle determinants of estrogen metabolism profiles
Summary
Breast cancer is the most common malignancy among women in the United States. Over 200 independent breast cancer susceptibility loci have been identified (1,2), though the underlying biological mechanisms remain elusive. Previous animal and epidemiologic studies have suggested estrogen metabolites, generated from irreversible hydroxylation of the parent estrogens (i.e., estrone and estradiol), may play a role in the etiology of breast cancer (3-11). A recent study leveraging data of 1,298 breast cancer cases and 1,524 matched controls from four prospective cohorts has shown that more extensive 2-hydroxlyation of parent estrogens (measured by ratios of 2-pahtway to total estrogen/estrogen metabolites or 2-pathway to parent estrogens) was inversely associated with breast cancer risk (12). However, it remains unclear if (1) the observed association related to the 2-hydroxylation pathway is causally related to cancer risk; and (2) the 2-pathway estrogen metabolizing patterns could be modified via lifestyle alterations. To bridge these knowledge gaps, we propose a large-scale study to systematically search for genetic variants and lifestyle factors for estrogen metabolism profiles. We hope to include the PLCO as part of this project and expect that the PLCO will contribute ~1200 subjects with available pre-diagnostic parent estrogens/estrogen metabolite measurements and genotyping data. We believe that the proposed study should produce substantial new knowledge to help better understand breast cancer etiology and develop more cost-effective tools for cancer risk assessment and prevention.
Aims

1) Perform a genome-wide association study (GWAS) to identify genetic variants associated with estrogen metabolizing patterns, particularly those of 2-pathway estrogen metabolites. Identified variants will be used to construct genetic instruments for subsequent Mendelian randomization analyses.

2) Evaluate associations of selected lifestyle factors, including dietary intake, physical activity, body weight, tobacco smoking and alcohol consumption, with estrogen metabolism profiles. We hypothesize that more extensive 2-pathway hydroxylation may be associated with lifestyle factors related to a reduced risk of breast cancer. We will also derive a lifestyle pattern characterizing the 2-pathway estrogen metabolizing patterns and evaluate its association with cancer risk in future studies.

3) Prostate cancers and sex hormones will also be analyzed.

References
1. Shu X, Long J, Cai Q, Kweon SS, Choi JY, Kubo M, et al. Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants. Nat Commun 2020;11(1):1217 doi 10.1038/s41467-020-15046-w.
2. Zhang H, Ahearn TU, Lecarpentier J, Barnes D, Beesley J, Qi G, et al. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nat Genet 2020;52(6):572-81 doi 10.1038/s41588-020-0609-2.
3. Zhu BT, Conney AH. Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis 1998;19(1):1-27 doi 10.1093/carcin/19.1.1.
4. Yager JD. Endogenous estrogens as carcinogens through metabolic activation. J Natl Cancer Inst Monogr 2000(27):67-73 doi 10.1093/oxfordjournals.jncimonographs.a024245.
5. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med 2006;354(3):270-82 doi 10.1056/NEJMra050776.
6. Samavat H, Kurzer MS. Estrogen metabolism and breast cancer. Cancer Lett 2015;356(2 Pt A):231-43 doi 10.1016/j.canlet.2014.04.018.
7. Eliassen AH, Spiegelman D, Xu X, Keefer LK, Veenstra TD, Barbieri RL, et al. Urinary estrogens and estrogen metabolites and subsequent risk of breast cancer among premenopausal women. Cancer Res 2012;72(3):696-706 doi 10.1158/0008-5472.CAN-11-2507.
8. Fuhrman BJ, Schairer C, Gail MH, Boyd-Morin J, Xu X, Sue LY, et al. Estrogen metabolism and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 2012;104(4):326-39 doi 10.1093/jnci/djr531.
9. Falk RT, Brinton LA, Dorgan JF, Fuhrman BJ, Veenstra TD, Xu X, et al. Relationship of serum estrogens and estrogen metabolites to postmenopausal breast cancer risk: a nested case-control study. Breast Cancer Res 2013;15(2):R34 doi 10.1186/bcr3416.
10. Dallal CM, Tice JA, Buist DS, Bauer DC, Lacey JV, Jr., Cauley JA, et al. Estrogen metabolism and breast cancer risk among postmenopausal women: a case-cohort study within B~FIT. Carcinogenesis 2014;35(2):346-55 doi 10.1093/carcin/bgt367.
11. Moore SC, Matthews CE, Ou Shu X, Yu K, Gail MH, Xu X, et al. Endogenous Estrogens, Estrogen Metabolites, and Breast Cancer Risk in Postmenopausal Chinese Women. J Natl Cancer Inst 2016;108(10) doi 10.1093/jnci/djw103.
12. Sampson JN, Falk RT, Schairer C, Moore SC, Fuhrman BJ, Dallal CM, et al. Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women. Cancer Res 2017;77(4):918-25 doi 10.1158/0008-5472.CAN-16-1717.

Collaborators

Wei Zheng, M.D., Ph.D., M.P.H. (Vanderbilt University Medical Center)