Abstract
BackgroundObservational studies and randomized trials have suggested that estrogens and/or progesterone may lower the risk for colorectal cancer. Inherited variation in the sex-hormone genes may be one mechanism by which sex hormones affect colorectal cancer, although data are limited.MethodWe conducted a comprehensive evaluation of single nucleotide polymorphisms (SNPs) in genes encoding 3 hormone receptors (ESR1, ESR2, PGR) and 5 hormone synthesizers (CYP19A1 and CYP17A1, HSD17B1, HSD17B2, HSD17B4) among 427 women with incident colorectal cancer and 871 matched controls who were Caucasians of European ancestry from 93676 postmenopausal women enrolled in the Women's Health Initiative Observational cohort. A total of 242 haplotype-tagging and functional SNPs in the 8 genes were included for analysis. Unconditional logistic regression with adjustment for age and hysterectomy status was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).ResultsWe observed a weak association between the CYP17A1 rs17724534 SNP and colorectal cancer risk (OR per risk allele (A) = 1.39, 95% CI = 1.09-1.78, corrected p-value = 0.07). In addition, a suggestive interaction between rs17724534 and rs10883782 in 2 discrete LD blocks of CYP17A1 was observed in relation to colorectal cancer (empirical p value = 0.04). Moreover, one haplotype block of CYP19A1 was associated with colorectal cancer (corrected global p value = 0.02), which likely reflected the association with the tagging SNP, rs1902584, in the block.ConclusionOur findings offer some support for a suggestive association of CYP17A1 and CYP19A1 variants with colorectal cancer risk.
Highlights
Observational studies and randomized trials have suggested that estrogens and/or progesterone may lower the risk for colorectal cancer
We observed a weak association between the CYP17A1 rs17724534 Single nucleotide polymorphism (SNP) and colorectal cancer risk (OR per risk allele (A) = 1.39, 95% confidence intervals (CIs) = 1.09-1.78, corrected p-value = 0.07)
One haplotype block of CYP19A1 was associated with colorectal cancer, which likely reflected the association with the tagging SNP, rs1902584, in the block
Summary
Observational studies and randomized trials have suggested that estrogens and/or progesterone may lower the risk for colorectal cancer. At least 3 phase-design genomewide association scan (GWAS) studies of colorectal cancer have been undertaken, which identified several novel susceptibility loci mapping to 1q41, 3q26.2, 8q23.3, 8q24, 10p14, 12q13.13, 14q22.2, 15q13, 16q22.1, 18q21, 19q13.1, 20p12.3, and 20q13.33 [13,14,15,16,17,18,19,20] None of these detected regions harbor genes involved in sex hormone synthesis or actions. Two of the nearest sexhormone genes, HSD17B2 (16q24.1) and CYP19A1 (15q21.1), are at least 13 million basepairs (bp) distant from the GWAS loci These observations suggest that the individual effect of hormone-related genes on colorectal cancer risk is not large enough to be detected at the genome-wide significance level (ie, p value
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