Abstract

The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the final step in the biosynthesis of estrogens. In this study, we used a systematic two-step approach that included gene resequencing and a haplotype-based analysis to comprehensively survey common genetic variation across the CYP19A1 locus in relation to circulating postmenopausal steroid hormone levels and breast cancer risk. This study was conducted among 5,356 invasive breast cancer cases and 7,129 controls comprised primarily of White women of European descent drawn from five large prospective cohorts within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A high-density single-nucleotide polymorphism (SNP) map of 103 common SNPs (> or =5% frequency) was used to identify the linkage disequilibrium and haplotype patterns across the CYP19A1 locus, and 19 haplotype-tagging SNPs were selected to provide high predictability of the common haplotype patterns. We found haplotype-tagging SNPs and common haplotypes spanning the coding and proximal 5' region of CYP19A1 to be significantly associated with a 10% to 20% increase in endogenous estrogen levels in postmenopausal women [effect per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 4.4 x 10(-15)]. No significant associations were observed, however, with these SNPs or common haplotypes and breast cancer risk. Thus, although genetic variation in CYP19A1 produces measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer.

Highlights

  • A doubling of postmenopausal endogenous levels is estimated to increase breast cancer risk by f30% [1]

  • This study includes five breast cancer case-control studies nested within established prospective cohorts: American Cancer Society Cancer Prevention Study II [9], European Prospective Investigation into Cancer and Nutrition (EPIC) cohort [10], Harvard Nurses’ Health Study (NHS; ref. 11); Women’s Health Study [12]; and Multiethnic Cohort Study (MEC; ref. 13) that represent the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (Supplementary Materials)

  • We found highly significant relationships (Table 1) between tag single-nucleotide polymorphism (SNP) and circulating estrogen levels among postmenopausal women with the strongest effects observed with SNPs in linkage disequilibrium (LD) blocks 3 and 4 (P values for global effects by block for E2/E1: block 1, 0.24/0.03; block 2, 0.16/1.4 Â 10À5; block 3, 7.2 Â 10À9/6.2 Â 10À9; block 4, 5.9 Â 10À11/1.3 Â 10À12)

Read more

Summary

Introduction

A doubling of postmenopausal endogenous levels is estimated to increase breast cancer risk by f30% [1]. CYP19A1 spans f123 kb at 15q21.1 and comprises nine coding exons (II–X) and several alternative, untranslated first exons that are expressed under the control of tissue-specific promoters [2]. Studies have suggested that variation at this locus may be a marker of circulating estrogen levels in postmenopausal women and contribute to risk of breast cancer [3,4,5,6,7,8]. A combination of genomic approaches is applied here; this includes resequencing of the coding exons and a linkage disequilibrium (LD)–based analysis to systematically search for markers of circulating steroid hormones and breast cancer risk at the CYP19A1 locus

Materials and Methods
 10À6
Results and Discussion
Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.