Estrogen and progesterone-related gene variants and colorectal cancer risk in women
ABSTRACT Observational 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.
We 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).
We 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.
Our findings offer some support for a suggestive association of CYP17A1 and CYP19A1 variants with colorectal cancer risk.
Full-textDOI: · Available from: Barbara B Cochrane, May 29, 2015
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ABSTRACT: Although somatic alterations in CAG repeats in the androgen receptor (AR) gene have been suggested to predispose to colorectal cancer (CRC), less is known about AR in CRC carcinogenesis. Due to lack of relevant analysis on CAG repeat length and AR expression in CRC, we aimed to investigate the prognostic value of polymorphic CAG and protein expression of the AR gene in CRC patients. A case-control study was carried out on 550 CRC patients and 540 healthy controls to investigate whether polymorphic CAG within the AR gene is linked to increased risk for CRC. Polymorphic CAG and AR expression were analyzed to clarify their relationship with clinicopathological and prognostic factors in CRC patients. The study showed that the AR gene in CRC patients had a longer CAG repeat sequence than those in the control group, as well as increased risk for CRC among females (P = 0.013), males (P = 0.002), and total CRC population (P < 0.001), respectively. AR expression exhibited a significant difference in long CAG repeat sequence among males (P < 0.001), females (P < 0.001), and total CRC study population (P < 0.001). Both long CAG repeat sequence and negative AR expression were associated with a short 5-year overall survival (OS) rate in CRC. Long CAG repeat sequences and absence of AR expression were closely related to the development of CRC. Both long CAG and decreased AR expression were correlated with the poor 5-year OS in CRC patients. Copyright © 2015, American Association for Cancer Research.Molecular Cancer Therapeutics 01/2015; 14(4). DOI:10.1158/1535-7163.MCT-14-0620 · 6.11 Impact Factor
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ABSTRACT: Sex steroid hormones play a role in colorectal cancer (CRC) development, but little is known about their influence on tumor progression and metastasis. Because catechol-O-methyltransferase (COMT; 22q11.21) activity is an important component of estrogen-mediated carcinogenesis, we hypothesized that germline variation in COMT may be associated with CRC survival. We identified 10 single nucleotide polymorphisms that tagged variation across two isoforms of COMT in 2,458 women with CRC from the Nurses' Health Study, Postmenopausal Hormones Supplementary Study to the Colon Cancer Family Registry, VITamins And Lifestyle Study, and Women's Health Initiative. All four studies participated in the Genetics and Epidemiology of Colorectal Cancer Consortium. During a median follow-up of 7 years across all studies, there were 799 deaths, including 566 deaths from CRC. Based on multiple comparisons, no associations between single nucleotide polymorphisms and CRC-specific or overall survival reached statistical significance, including the well-characterized Val108/158Met polymorphism (rs4680; CRC-specific survival: hazard ratio per minor allele, 1.04; 95% CI, 0.92-1.17; overall survival: hazard ratio per minor allele, 1.01; 95% CI, 0.90-1.14). In this large study of women with CRC, we find no evidence that common inherited variation in COMT is associated with survival time after diagnosis.Menopause (New York, N.Y.) 07/2013; DOI:10.1097/GME.0b013e31829e498d · 2.81 Impact Factor
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ABSTRACT: CYP19A1 facilitates the bioconversion of estrogens from androgens. CYP19A1 intron single nucleotide polymorphisms (SNPs) may alter mRNA splicing, resulting in altered CYP19A1 activity, and potentially influencing disease susceptibility. Genetic studies of CYP19A1 SNPs have been well documented in populations of European ancestry; however, studies in populations of African ancestry are limited. In the present study, ten 'candidate' intronic SNPs in CYP19A1 from 125 African Americans (AA) and 277 European Americans (EA) were genotyped and their frequencies compared. Allele frequencies were also compared with HapMap and ASW 1000 Genomes populations. We observed significant differences in the minor allele frequencies between AA and EA in six of the ten SNPs including rs10459592 (p<0.0001), rs12908960 (p<0.0001), rs1902584 (p = 0.016), rs2470144 (p<0.0001), rs1961177 (p<0.0001), and rs6493497 (p = 0.003). While there were no significant differences in allele frequencies between EA and CEU in the HapMap population, a 1.2- to 19-fold difference in allele frequency for rs10459592 (p = 0.004), rs12908960 (p = 0.0006), rs1902584 (p<0.0001), rs2470144 (p = 0.0006), rs1961177 (p<0.0001), and rs6493497 (p = 0.0092) was observed between AA and the Yoruba (YRI) population. Linkage disequilibrium (LD) blocks and haplotype clusters that is unique to the EA population but not AA was also observed. In summary, we demonstrate that differences in the allele frequencies of CYP19A1 intron SNPs are not consistent between populations of African and European ancestry. Thus, investigations into whether CYP19A1 intron SNPs contribute to variations in cancer incidence, outcomes and pharmacological response seen in populations of different ancestry may prove beneficial.PLoS ONE 02/2015; 10(2):e0117347. DOI:10.1371/journal.pone.0117347 · 3.53 Impact Factor