Estrogen receptor polymorphisms and the risk of endometrial cancer

Abstract

Objective There is evidence that estrogens and some of their metabolites are involved in endometrial cancer pathogenesis. As estrogens mediate their effects via the estrogen receptors, ESR1 and ESR2, the objective of this investigation was to determine whether six single nucleotide polymorphisms (SNPs) in these two genes were over-represented in a population of endometrial cancer patients compared with a healthy matched control population, thereby associating differences in these genes with endometrial cancer.Design The study is a case-control investigation large enough to detect a two-fold increased risk, assuming a dominant genetic model, with P = 0.05 and 80% power.Setting The study and control populations were all from the Hunter-New England region of New South Wales, Australia collected between the years 1992 and 2005.Population The study consisted of 191 endometrial cancer patients and 291 healthy controls matched for gender and age.Methods Two SNPs in ESR1 and four SNPs in ESR2 were genotyped using PCR-based restriction fragment length polymorphism analysis and real-time PCR. Odds ratios were calculated using unconditional logistic regression and SIMHAP was used for haplotype analysis, adjusting for potential endometrial cancer risk factors. Kaplan-Meier survival analysis, Cox regression and t tests were used to examine the patient's age of diagnosis of endometrial cancer and genotype.Main outcome measures Over-representation of ESR1 and ESR2 polymorphisms in the endometrial cancer population compared with the control population indicates an involvement in the development and/or progression of disease.Results Two ESR1 (rs2234693 and rs9340799) and two ESR2 (rs1255998 and rs944050) polymorphisms were associated with an increased risk of endometrial cancer. Following adjustment for risk factors, the association with the ESR1 and ESR2 polymorphisms (rs2234693, rs1255998 and rs944050) remained highly significant. Haplotype analysis revealed that carriers of the ESR1 haplotype (variant alleles; rs2234693 and rs9340799) and the ESR2 haplotype (variant allele; rs1255998 and wild-type alleles; rs944050, rs4986938 and rs1256049) were at an increased risk (OR 1.862, P = 0.013 and OR 1.918, P = 0.046 respectively). This risk was even greater in women carrying both risk haplotypes (OR 5.041, P = 0.007).Conclusions Our data suggest that the ESR1 (rs2234693 and rs9340799) and the ESR2 (rs1255998 and rs944050) polymorphisms may be associated with an increased risk of developing endometrial cancer.

Polymorphisms in genes of the steroid hormone biosynthesis and metabolism pathways and endometrial cancer risk

“…The study population has been described previously [19][20][21][22]. Briefly, the initial population consisted of 451 consecutive Caucasian women who were registered at the Hunter Centre for Gynaecological Cancer, John Hunter Hospital, Newcastle, New South Wales, Australia between the years 1992 and 2005.…”

Variants on ESR1 and their Association with Prostate Cancer Risk: A Meta-analysis

“…From a meta-analysis conducted by Ioannidis et al have found that for women who were homozygous for the absence of an XbaI recognition site, the adjusted odds of all fractures were reduced by 19% (OR = 0.81, 95% CI = 0.71-0.93) and vertebral fractures by 35% (OR = 0.65, 95% CI = 0.49-0.87) (Ioannidis et al, 2004). Wedren et al found that allele C was associated with a significant reduced risk for endometrial cancer risk (Wedren et al, 2008), but another study conducted by Ashton et al found that allele C was a risk factor for endometrial cancer risk, which may be due to the population diversity (Ashton et al, 2009). Wang et al found that the variant was associated with a protective effect on breast cancer (Wang et al, 2007); however, a meta-analysis suggested no correlation for the variant and breast cancer risk was found (Li et al, 2010).…”

Association of the estrogen receptor-β gene RsaI and AluI polymorphisms with human idiopathic thin endometrium

“…Synonymous mutations have been postulated to influence gene transcription through several means (Setiawan et al, 2004): the local concentration of transfer RNA varies for different codons; the mutation on messenger RNA (mRNA) may induce the formation of hairpins and result in mRNA instability or transcriptional inactivity; or the polymorphism gives rise to linkage disequilibrium with the other site mutation, such as the polymorphism on the ER-β gene 5ꞌG1082A and 3ꞌ untranslated region A1730G, which cross-links with the polymorphism on the splicing site of the 8th exon and affects the splicing of the 8th exon. Additionally, the polymorphism can induce an alteration in the secondary structure of ER-β mRNA and lead to changes at the mRNA level, affecting synthesis, splicing, maturation, translocation, translation, and degradation, among other processes (Aschim et al, 2005;Ashton et al, 2009;Safarinejad et al, 2010).…”