Progesterone receptor gene variants and risk of endometrial cancer

Abstract

Prolonged excessive estrogen exposure unopposed by progesterone is widely accepted to be a risk factor for endometrial cancer development. The physiological function of progesterone is dependent upon the presence of its receptor [progesterone receptor (PGR)] and several studies have reported single nucleotide polymorphisms (SNPs) in the PGR gene to be associated with endometrial cancer risk. We sought to confirm the associations with endometrial cancer risk previously reported for four different PGR polymorphisms. A maximum of 2888 endometrial cancer cases and 4483 female control subjects from up to three studies were genotyped for four PGR polymorphisms (rs1042838, rs10895068, rs11224561 and rs471767). Logistic regression with adjustment for age, study, ethnicity and body mass index was performed to calculate odds ratios (ORs) and associated 95% confidence intervals (CIs) and P-values. Of the four SNPs investigated, only rs11224561 in the 3' region of the PGR gene was found to be significantly associated with endometrial cancer risk. The A allele of the rs11224561 SNP was associated with increased risk of endometrial cancer (OR per allele 1.31; 95% CI 1.12-1.53, P = 0.001, adjusted for age and study), an effect of the same magnitude and direction as reported previously. We have validated the endometrial cancer risk association with a tagSNP in the 3' untranslated region of PGR previously reported in an Asian population. Replication studies will be required to refine the risk estimate and to establish if this, or a correlated SNP, is the underlying causative variant.

Selected polymorphisms in sex hormone-related genes, circulating sex hormones and risk of endometrial cancer

“…The Alu insertion has been shown to reduce transcript stability, and the amino acid substitution (V660L) to result in lower efficiency in opposing proliferation of cells expressing the A isoform of the receptor [14], the main isoform mediating the anti-proliferative effects of progesterone in the endometrium [42]. The suggestive increase in risk we observed with PGR rs1042838 is consistent with these observations, as well as with results of some [6, 16, 25], but not all [26, 43, 44], other epidemiologic studies. The large study conducted by Lee et al, which examined 17 haplotype-tagging SNPs in the PGR gene, reported that the PROGINS allele, and haplotypes containing the PROGINS allele, were associated with increased endometrial cancer risk [25].…”

Genome-Wide Association Study Identifies a Possible Susceptibility Locus for Endometrial Cancer

“…Over the past 10 years, a number of studies have reported that certain genetic variants are associated with endometrial cancer risk, including polymorphisms in genes involved in estrogen metabolism (3). However, very few of these associations have been confirmed (4–7). Given that almost all previous studies used the candidate-gene approach, in which only a limited number of genetic variants are investigated, and the choice of genes is driven by our limited knowledge of cancer biology, more comprehensive genetic investigations of endometrial cancer risk are urgently needed.…”

Association of +331G/A PgR Polymorphism with Susceptibility to Female Reproductive Cancer: Evidence from a Meta-Analysis

“…Nineteen studies met the inclusion criteria, the characteristics of which are reported in Table 1. Of these 19 studies, 10 were breast cancer (BC) studies in which all of the patients were of European ethnicity [11], [16]–[24]; six were ovarian cancer (OC) studies that only included patients of European origin [10], [17], [20], [25], [26], [27] and three studies were endometrial cancer (EC) studies, which enrolled patients of different ethnic groups [28], [29], [30].…”