Common genetic variation in the sex hormone metabolic pathway and endometrial cancer risk: Pathway-based evaluation of candidate genes

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20852, USA.
Carcinogenesis (Impact Factor: 5.33). 05/2010; 31(5):827-33. DOI: 10.1093/carcin/bgp328
Source: PubMed


Estrogen plays a major role in endometrial carcinogenesis, suggesting that common variants of genes in the sex hormone metabolic pathway may be related to endometrial cancer risk. In support of this view, variants in CYP19A1 [cytochrome P450 (CYP), family 19, subfamily A, polypeptide 1] have been associated with both circulating estrogen levels and endometrial cancer risk. Associations with variants in other genes have been suggested, but findings have been inconsistent.
We examined 36 sex hormone-related genes using a tagging approach in a population-based case-control study of 417 endometrial cancer cases and 407 controls conducted in Poland. We evaluated common variation in these genes in relation to endometrial cancer risk using sequential haplotype scan, variable-sized sliding window and adaptive rank-truncated product (ARTP) methods.
In our case-control study, the strongest association with endometrial cancer risk was for AR (androgen receptor; ARTP P = 0.006). Multilocus analyses also identified boundaries for a region of interest in AR and in CYP19A1 around a previously identified susceptibility loci. We did not find evidence for consistent associations between previously reported candidate single-nucleotide polymorphisms in this pathway and endometrial cancer risk.
In summary, we identified regions in AR and CYP19A1 that are of interest for further evaluation in relation to endometrial cancer risk in future haplotype and subsequent fine mapping studies in larger study populations.

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    • "A recent case-control study of polymorphisms in 391 EC cases and 712 individually-matched controls found that CYP19A1 variants are associated with increased risk of EC (Lundin, et al. 2012). Interestingly, in an extensive analysis of common genetic variation of 36 sex-hormone related genes by Yang et al, genetic variation in AR was significantly associated (p=0.006) with increased risk of EC 410 (Yang, et al. 2010). "
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    ABSTRACT: Endometrial and ovarian cancers are common gynecological malignancies. The impact of androgen action in these cancers is poorly understood however there is emerging evidence to suggest that targeting androgen signalling may be of therapeutic benefit. Epidemiological evidence suggests that there is an increased risk of endometrial cancer associated with exposure to elevated levels of androgens and genetic variants in genes related to both androgen biosynthesis and action are associated with increased risk of both endometrial and ovarian cancer. Androgen receptors may be a potential therapeutic target in endometrial cancer due to reported anti-proliferative activities of androgens. In contrast, androgens may promote growth of some ovarian cancers and anti-androgen therapy has been proposed. Introduction of new therapies targeting androgen receptors expressed in endometrial or ovarian cancers will require a much greater understanding of the impacts of cell context-specific androgen receptor-dependent signalling and how androgen receptors can cross-talk with other steroid receptors during progression of disease. This review considers the evidence that androgens may be important in the aetiology of endometrial and ovarian cancers with discussion of evidence for androgen action in normal and malignant endometrial and ovarian tissue.
    Full-text · Article · Mar 2014 · Endocrine Related Cancer
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    • "The details of the selection process were presented in a flow chart in Figure 1. Finally, thirteen case-control studies including 7,649 cases and 16,855 controls met the inclusion criteria in this meta-analysis [7], [8], [17]–[27]. The publication years of the involved studies ranged from 2000 to 2012. "
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    ABSTRACT: Emerging evidence indicates that common functional polymorphisms in the estrogen receptor 1 (ESR1) gene may have an impact on an individual's susceptibility to endometrial cancer, but individually published results are inconclusive. The aim of this meta-analysis is to derive a more precise estimation of the associations between eight polymorphisms in the ESR1 gene and endometrial cancer risk. A literature search of PubMed, Embase, Web of Science and China Biology Medicine (CBM) databases was conducted on publications published before November 1(st), 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistical analyses were performed using the STATA 12.0 software. Thirteen case-control studies were included with a total of 7,649 endometrial cancer cases and 16,855 healthy controls. When all the eligible studies were pooled into the meta-analysis, the results indicated that PvuII (C>T) polymorphism was associated with an increased risk of endometrial cancer, especially among Caucasian populations. There were also significant associations between rs3020314 (C>T) polymorphism and an increased risk of endometrial cancer. Furthermore, rs2234670 (S/L) polymorphism may decrease the risk of endometrial cancer. However, no statistically significant associations were found in XbaI (A>G), Codon 325 (C>G), Codon 243 (C>T), VNTR (S/L) and rs2046210 (G>A) polymorphisms. The current meta-analysis suggests that PvuII (C>T) and rs3020314 (C>T) polymorphisms may be risk factors for endometrial cancer, especially among Caucasian populations.
    Preview · Article · Apr 2013 · PLoS ONE
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    • "Study participants were Chinese (for ESCC and GCA studies) or whites (all other studies). The design of these studies included nested case–control (RCC (1994); Prorok et al, 2000; Han et al, 2012), CRC, CA (Gao et al, 2011)), population-based case–control (EC (Yang et al, 2010a)), hospital-based case–control (OS (Troisi et al, 2006; Mirabello et al, 2011)), and case–control studies of mixed design (ThC (Neta et al, 2012), ESCC and GCA (Blot et al, 1993; Gao et al, 2009)). After excluding subjects with a low genotyping completion rate (o80%), the final analysis for each tumour outcome included 437 RCC cases and 1603 controls; 417 EC cases and 407 controls; 344 ThC cases and 452 controls; 393 CRC cases and 434 controls; 1234 CA cases and 1368 controls; 1027 ESCC cases and 1452 controls; 753 GCA cases and 1452 controls; 96 OS cases and 1428 controls. "
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    ABSTRACT: Background: The chromosome 9p21.3 region has been implicated in the pathogenesis of multiple cancers. Methods: We systematically examined up to 203 tagging SNPs of 22 genes on 9p21.3 (19.9-32.8 Mb) in eight case-control studies: thyroid cancer, endometrial cancer (EC), renal cell carcinoma, colorectal cancer (CRC), colorectal adenoma (CA), oesophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma and osteosarcoma (OS). We used logistic regression to perform single SNP analyses for each study separately, adjusting for study-specific covariates. We combined SNP results across studies by fixed-effect meta-analyses and a newly developed subset-based statistical approach (ASSET). Gene-based P-values were obtained by the minP method using the Adaptive Rank Truncated Product program. We adjusted for multiple comparisons by Bonferroni correction. Results: Rs3731239 in cyclin-dependent kinase inhibitors 2A (CDKN2A) was significantly associated with ESCC (P=7 × 10(-6)). The CDKN2A-ESCC association was further supported by gene-based analyses (Pgene=0.0001). In the meta-analyses by ASSET, four SNPs (rs3731239 in CDKN2A, rs615552 and rs573687 in CDKN2B and rs564398 in CDKN2BAS) showed significant associations with ESCC and EC (P<2.46 × 10(-4)). One SNP in MTAP (methylthioadenosine phosphorylase) (rs7023329) that was previously associated with melanoma and nevi in multiple genome-wide association studies was associated with CRC, CA and OS by ASSET (P=0.007). Conclusion: Our data indicate that genetic variants in CDKN2A, and possibly nearby genes, may be associated with ESCC and several other tumours, further highlighting the importance of 9p21.3 genetic variants in carcinogenesis.
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