Associations between <i>ERα, ERβ</i>, and <i>AR</i> Genotypes and Colon and Rectal Cancer

Slattery, Martha L.; Sweeney, Carol; Murtaugh, Maureen A.; Ni, Khe; Wolff, Roger K.; Potter, John D.; Caan, Bette J.; Samowitz, Wade S.

doi:10.1158/1055-9965.epi-05-0514

Cited by 89 publications

(98 citation statements)

References 38 publications

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“…Another study of 1021 female cases and 1798 controls did not assess effect modification directly related to MHT use but compared the risk of CRC associated with polymorphisms in the ERa, ERb, and androgen receptor gene in 'estrogen negative' (postmenopausal women not using MHT) and in 'estrogen positive' women (who were either premenopausal or used MHT). They reported significantly stronger associations of two ERb gene polymorphisms, the SNP rs1256049 and a CA repeat in intron 5, with the 'estrogen negative' group (Slattery et al 2005). The variant rs1256049 was not included in this study.…”

Section: Discussionmentioning

confidence: 89%

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Modification of menopausal hormone therapy-associated colorectal cancer risk by polymorphisms in sex steroid signaling, metabolism and transport related genes

Rudolph

Sainz

Hein

et al. 2011

Endocrine Related Cancer

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The mechanisms underlying the association of menopausal hormone therapy (MHT) with reduced colorectal cancer (CRC) risk are unknown and the identification of genetic modifiers may yield further insight. We explored the effect modification of MHT-associated CRC risk in postmenopausal women by 47 polymorphisms with known or putative functional relevance in 16 candidate genes related to hormone metabolism (COMT, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP17A1, GSTP, and HSD17B1), transport (ABCB1), and signaling (ESR1, ESR2, SHBG, PGR, and NR1I2). A total of 685 CRC patients and 684 healthy controls from a German population-based case-control study (DACHS) were genotyped. Multiplicative statistical interaction between polymorphisms and ever MHT use as well as duration of use was assessed using multivariate logistic regression. CRC risk associated with ever MHT use as well as with duration was significantly modified by rs1202168 in the transporter gene ABCB1 (P interactionZ0.04). The MHT-associated risk reduction was not significant in homozygous non-carriers (odds ratio (OR) ever useZ0.84, 95% confidence interval (CI) 0.53-1.34; OR per 5 year durationZ0.94, 95% CI 0.83-1.08), while homozygous carriers of the minor T allele had a 57% lower risk with ever use of MHT (95% CI 0.21-0.88) and a 22% lower risk per 5 years of MHT use (95% CI 0.62-0.97). Significant effect modification was also observed for the ESR1_rs910416 polymorphism (P interactionZ0.03 for ever use and 0.07 for duration of use), whereby the decreased risk was attenuated in homozygous carriers of the minor C allele (OR ever useZ0.87, 95% CI 0.48-1.60, OR per 5 year durationZ0.99, 95% CI 0.83-1.18). Results of this exploratory study provide first evidence that polymorphisms in genes related to estrogen transport and signaling may modify MHT-associated CRC risk but warrant replication in an independent population.

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Section: Discussionmentioning

confidence: 89%

“…The effect of estrogen on tumor development may be mediated through its receptors (Slattery et al 2005, Kennelly et al 2008. Both estrogen receptor a (ERa) and ERb can be detected in colon tissue, while ERb is found to be more prevalent than ERa (Foley et al 2000, Konstantinopoulos et al 2003, Jassam et al 2005.…”

Section: Introductionmentioning

confidence: 99%

Modification of menopausal hormone therapy-associated colorectal cancer risk by polymorphisms in sex steroid signaling, metabolism and transport related genes

Rudolph

Sainz

Hein

et al. 2011

Endocrine Related Cancer

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“…We have shown previously that the AR gene interacts significantly with gender. 34 The reason for the significant interaction between the AR gene and vitamin D intake and sunshine exposure in altering colorectal cancer risk among men is not clear. This difference in association could be from differences in sunshine exposure in men and women, and that a certain dose of exposure is needed to have a meaningful effect.…”

Section: Discussionmentioning

confidence: 99%

Associations between vitamin D, vitamin D receptor gene and the androgen receptor gene with colon and rectal cancer

Slattery

Sweeney

Murtaugh

et al. 2006

Intl Journal of Cancer

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The transcriptional activity of the vitamin D receptor (VDR) gene is regulated, at least in part, by the androgen receptor (AR) gene. We evaluate how the number of polyglutamine (CAG) repeats of the AR gene influence colorectal cancer in conjunction with vitamin D, sunshine exposure and VDR. Studies of colon (1,580 cases and 1,968 controls) and rectal (797 cases and 1,016 controls) cancer were used. Vitamin D intake and average hours of sunshine exposure interacted with AR genotype in men. Men with low vitamin D intake or low levels of sunshine exposure who had 231 CAG repeats of the AR gene had the greatest risk of colon cancer. ORs for men with 23 or more CAG repeats of the AR gene and in the lowest tertile of vitamin D intake or sunshine exposure were 1.71 (95% CI 1.14, 2.56) and 1.51 (95% CI 1.09, 2.09). Men with high levels of sunshine exposure were at reduced risk of developing rectal cancer if they had 23 or more CAG repeats (OR 0.62 95% CI 0.39, 0.97) than if they had fewer than 23 CAG repeats. The FF genotype of the Fok1 VDR gene was associated with reduced risk of colon cancer among women with any allele of 231 CAG repeats (OR 0.62 95% CI 0.44, 0.88), whereas men with the LL/bb VDR genotypes were at reduced risk of rectal cancer if they also had 231 CAG repeats (OR 0.71 95% CI 0.48, 1.05) relative to men with fewer than 23 CAG repeats of the AR gene. These data provide support for the role of vitamin D and sunshine exposure in the etiology of colorectal cancer and suggest that AR gene may modulate the association. Vitamin D has been associated inconsistently with colorectal cancer. 10 Differences in relative risk could stem from many sources, including sunshine, a major source of vitamin D, not being considered as part of the risk factor equation. Several investigators have studied sunshine exposure independently to better understand the associations between vitamin D and colorectal cancer. 11-13 Polymorphisms of the VDR gene have also been studied in conjunction with colorectal cancer and adenomas, since it may play a key role in vitamin D signaling, which could further influence colorectal cancer risk. [14][15][16][17][18][19] Polymorphisms of the VDR gene that have been studied include a poly A repeat at the 3 0 untranslated region (3 0 UTR) of the gene, 2 polymorphisms at intron 8 (Bsm I and Apa I) and 1 in exon 9 (Taq I) that are in linkage-disequilibrium with each other. 17,20 These polymorphisms, either alone or in combination, have been associated with increased mRNA expression of the VDR gene and increased serum levels of 1,25-dihydroxy vitamin D. 21,22 At the start site of the gene, a polymorphism detected with a Fok I digest has also been studied and has been shown to be not in linkage disequilibrium with the other variants. 17 A study conducted in human fibroblast cell lines found higher vitamin D hormone activity for the F allele than for the f allele. 23 One study showed that the ff genotype of the Fok I polymorphism increased risk of colorectal cancer, 18 whereas another showed that it w...

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“…The h 3 -adrenergic receptor (ADRB3) W64R (T>C) variant was assessed by PCR and BstNI restriction digest as described previously (24). Estrogen receptor a (ESR1) 351 A>G was evaluated by PCR and XbaI restriction (25,26). The insulin-like growth factor binding protein 3 (IGFBP3) À202 C>A substitution was detected by PCR and digestion with the Alw21I restriction enzyme (27).…”

Section: Methodsmentioning

confidence: 99%

Genetic Admixture among Hispanics and Candidate Gene Polymorphisms: Potential for Confounding in a Breast Cancer Study?

Sweeney¹,

Wolff²,

Byers

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Hispanics in the U.S. Southwest have genetic ancestry from Europeans and from American Indians, two groups with markedly different breast cancer incidence rates. Genetic admixture may therefore bias estimates of associations between candidate cancer susceptibility genes and breast cancer in Hispanics. We estimated genetic admixture using 15 ancestry-informative markers for 1,239 Hispanics and 2,505 non-Hispanic Whites in a breast cancer case-control study in the Southwest, the Four Corners Study. Confounding risk ratios (CRR) were calculated to quantify potential bias due to admixture. Genetic admixture was strongly related to selfreported race and ethnic background (P < 0.0001). Among Hispanic controls, admixture was significantly associated with allele frequency for 5 of 11 candidate gene single nucleotide polymorphisms (SNP) examined. Hispanics in the highest versus the lowest quintile of American Indian admixture had higher mean body mass index at age 30 years (25.4 versus 23.6 kg/m 2 ; P = 0.003), shorter mean height (1.56 versus 1.58 m; P = 0.01), higher prevalence of diabetes (14.8% versus 7.2%; P = 0.04), and a larger proportion with less than a high school education (38.5% versus 23.2%; P = 0.001). Admixture was not associated with breast cancer risk among Hispanics (P = 0.65). CRRs for potential bias to candidate SNP-breast cancer risk ratios ranged from 0.99 to 1.01. Thus, although genetic admixture in Hispanics was associated with exposures, confounding by admixture was negligible due to the null association between admixture and breast cancer. CRRs from simulated scenarios indicated that appreciable confounding by admixture would occur only when within-group candidate SNP allele frequency differences are much larger than any that we observed. (Cancer Epidemiol Biomarkers Prev 2007;16(1):142 -50)

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Associations between ERα, ERβ, and AR Genotypes and Colon and Rectal Cancer

Cited by 89 publications

References 38 publications

Modification of menopausal hormone therapy-associated colorectal cancer risk by polymorphisms in sex steroid signaling, metabolism and transport related genes

Modification of menopausal hormone therapy-associated colorectal cancer risk by polymorphisms in sex steroid signaling, metabolism and transport related genes

Associations between vitamin D, vitamin D receptor gene and the androgen receptor gene with colon and rectal cancer

Genetic Admixture among Hispanics and Candidate Gene Polymorphisms: Potential for Confounding in a Breast Cancer Study?

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