AS192 - Estrogen and Progesterone-related Gene Variants and Colorectal Cancer Risk

This page provides study documentation for AS192.  For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

 

Investigator Names and Contact Information

Shumin M. Zhang, MD, ScD; shumin.zhang@channing.harvard.edu
 

Introduction/Intent

Accumulating evidence suggests that postmenopausal estrogen plus progestin therapy reduces the risk of colorectal cancer (CRC). This proposed study will evaluate whether common polymorphisms in the genes encoding estrogen and progesterone receptors (ESR1, ESR2, PGR), and enzymes responsible for critical steps in the conversion of progesterone to estrogens via androgens (CYP17A1, HSD17B2, CYP19A1) and for estrogen metabolism (CYP1A1, CYP1B1, COMT), are associated with CRC risk. Polymorphisms in these genes that cause functional variations in receptors and circulating and cellular levels of hormones may confer a predisposition to CRC.
 
We will first select the single nucleotide polymorphisms (SNPs) or repeat polymorphisms that have known or predicted functional consequences. We also will employ a haplotype-based method, which tests a subset of SNPs across the gene and relies on linkage disequilibrium (LD) between genotyped and unassayed SNPs, to detect new functional polymorphisms that cannot be predicted a priori. Selection of common SNPs to tag haplotypes for the proposed candidate genes will be based on the LD map that is unique to the Women’s Health Initiative (WHI) observational study (OS) cohort. This LD map will be constructed by genotyping common SNPs that are about 5-10 kb apart along the gene sequence in 50 randomly chosen controls.
 
A total of 650 cases and their two matched controls will then be identified in the WHI OS cohort of postmenopausal women with existent blood samples at baseline through 2005. We will use conditional logistic regression to test for associations between SNPs that may have functional significance and haplotype-tag SNPs in these genes and CRC risk. The WHI OS cohort is well characterized with respect to use of postmenopausal hormone therapy (HT) and environmental exposures, and has large numbers of confirmed CRC cases, which provides an extraordinary opportunity to examine interactions between these gene variants and HT use in relation to CRC risk. We will further explore interactions among these genes. The findings from this study will have substantial implications for our understanding of the effects of HT on CRC risk.
 
Aims
 
The WHI trial has shown that use of postmenopausal estrogen plus progestin therapy reduces CRC risk 1, 2. However, the underlying mechanisms by which estrogen and progesterone affect the development of CRC remain unclear. We propose to evaluate possible associations between CRC risk and common polymorphisms in the genes encoding estrogen receptors (ESRs), progesterone receptor (PGR), and enzymes responsible for critical steps in the conversion of progesterone to estrogens via androgens and for estrogen metabolism in the WHI OS cohort. We will further examine whether these associations are modified by use of estrogen plus progestin vs. estrogen alone. Finally, we will explore interactions among these candidate genes in relation to CRC risk. Findings from this proposed study may help explain the effects of postmenopausal estrogen plus progestin therapy on CRC risk observed in the WHI trial. The specific aims to be tested are as follows:
 
1.  Common polymorphisms in genes encoding ESR1, ESR2, PGR, and enzymes responsible for the conversion of progesterone to estrogens via androgens (CYP17A1, HSD17B2, and CYP19A1) and for estrogen metabolism (CYP1A1, CYP1B1, and COMT), are associated with CRC risk.
 
2.  The associations between polymorphisms in these estrogen and progesterone-related genes and CRC risk are modified by use of estrogen plus progestin vs. estrogen alone.
 
3. There are interactions between different polymorphisms in these estrogen and progesterone-related genes in relation to CRC risk.
 
Detailed list of polymorphisms
·          ESR1 (PVII; Xbal, rs2077647; Gly77Ser; rs1801132)
·          ESR2 (CA repeat; G1730A, rs1271572; rs944050; rs928554)
·          COMT (Val158Met)
·          CYP1A1 (MspI; Ile462Val, Thr461Asn; rs2606345),
·          CYP1B1 (Leu432Val; Asn453Ser, Ala119Ser; Arg48Gly)
·          CYP17A1 (T-34C, rs7097872; rs6892)
·          CYP19A1 ([TTTA]n repeat; Arg264cys; rs28757082; rs11636639; rs767199; rs4775936; rs700518)
·          HSD17B21 (Ser312Gly)
·          HSD17B4 (Arg106His; Trp511Arg; Ile559Val)
·          PGR (G+331A, Ala444Ser; rs518162; rs1042839; rs500760)
·          200-400 SNPs for haplotype analyses

 

Results/Findings

Some of the publications related to this ancillary study are:  

Ms1126 - Lin JH, Manson JE, Kraft P, Cochrane BB, Gunter MJ, Chlebowski RT, Zhang SM. Estrogen and progesterone-related gene variants and colorectal cancer risk in women. BMC Med Genet. 2011 May 31;12(1):78. [Epub ahead of print]

Ms1507 - Lin JH, Gunter MJ, Manson JE, Rexrode KM, Cook NR, Kraft P, Cochrane BB, Chlebowski RT, Ho GY, Zhang SM. The aromatase gene (CYP19A1) variants and circulating hepatocyte growth factor in postmenopausal women. PLoS One. 2012;7(7):e42079. Epub 2012 Jul 25

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.