ESR1 gene is critical for hormone binding, DNA binding, and activation of transcription because it encodes an estrogen receptor that is key in the mediation of hormonal response in estrogen-sensitive tissues 
. Thus, genetic mutations in ESR1 gene may contribute to its abnormal expression and are probably linked to increased risk of hormone-related cancers such as the breast, prostate, and endometrial cancers 
. Li et al performed a meta-analysis that evaluated the association between ESR1 gene polymorphisms and breast cancer risk in diverse populations 
. There results suggests that variant genotypes of PvuII and rs1801132 (Codon 325) may contribute to breast cancer susceptibility. Several ESR1 gene polymorphisms have been identified as candidates for prostate cancer susceptibility and among these, ESR1 PvuII and XbaI SNPs were suggested to possess significant associations with the development of prostate cancer 
. Many previous genetic studies have suggested that ESR1 gene polymorphisms may play an important role in endometrial carcinogenesis 
, while other studies found no convincing evidence of these polymorphisms in increasing endometrial cancer susceptibility 
. This controversy could be explained with several reasons, including the differences in study designs, sample size, ethnicity, statistical methods, etc. A recent meta-analysis by Wang et al indicated that PvuII polymorphism in the ESR1 gene could increase the risk of endometrial cancer, while XbaI polymorphism was not associated with susceptibility to endometrial cancer. However, they failed to assess the relationship between the other common polymorphisms in the ESR1 gene and endometrial cancer risk. This recent meta-analysis is aimed to update previous meta-analysis, as well as to provide a more comprehensive and reliable conclusion on the associations between eight common functional polymorphisms in the ESR1 gene and endometrial cancer susceptibility.
In this meta-analysis, 13 independent 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 showed that PvuII (C>T) polymorphism was associated with increased risk of endometrial cancer, especially among Caucasian populations, while similar associations were not observed among Asian populations. Although the exact function of PvuII (C>T) polymorphism in the development of endometrial cancer among different populations is not yet clear, a possible reason could be that inherited mutations in ESR1 might be associated with changes in estrogen metabolism and thereby could possibly explain inter-individual differences in disease incidences of endometrial cancer 
. However, no statistically significant associations were found between XbaI (A>G) polymorphism and endometrial cancer risk. The findings from this meta-analysis were consistent with the previous meta-analysis conducted by Wang et al, suggesting PvuII may be linked to the development of endometrial cancer. In addition to the previous meta-analysis, we also found a significant association between rs3020314 (C>T) polymorphism and an increased risk of endometrial cancer development, while the rs2234670 (S/L) polymorphism might decrease the risk of endometrial cancer development. Nevertheless, Codon 325 (C>G), Codon 243 (C>T), VNTR (S/L) and rs2046210 (G>A) polymorphisms showed no associations with the risk of endometrial cancer. These findings are consistent with the previous hypothesis that variability in the ESR1 gene may alter the risk of developing endometrial cancer, suggesting that they may be useful as biomarkers in predicting an individual’s genetic susceptibility to endometrial cancer.
Similar to other meta-analyses, our study also bears some limitations and shortages. First, the sample size is still relatively small and may not provide sufficient statistical power to estimate the correlations between ESR1 gene polymorphisms and endometrial cancer risk. Second, in this meta-analysis, potential sources of heterogeneity could include many other factors, such as age and sex structure, characteristics of healthy control, pre- and post-menopause, etc. Third, as a type of a retrospective study, a meta-analysis may encounter recall or selection bias, possibly influencing the reliability of our study results. Furthermore, in this meta-analysis, there is a significant difference in numbers between cancer cases and healthy controls, which may be one source of heterogeneity and may have some unfavorable effects on the reliability of our results. Finally, our lack of access to the original data from the studies limited further evaluation of potential interactions such as gene-environment and gene-gene interactions. In spite of these limitations, however, our present meta-analysis includes the largest number of eligible studies relevant to the relationship between ESR1 polymorphisms and endometrial cancer risk reported to date.
In conclusion, our meta-analysis suggests that PvuII (C>T) and rs3020314 (C>T) polymorphisms may be risk factors in endometrial cancer development, especially among Caucasian populations. These relationships will promise us a functional profiling of ESR1 gene and an understanding of the biological processes associated with endometrial cancer development and progression. It may also be further utilized as a diagnostic tool, as well as, an accurate determination of endocrine therapeutic strategies in endometrial cancer. However, further studies are still needed in order to validate the associations between polymorphisms in ESR1 and endometrial cancer.