Genetics of estrogen production linked to endometrial cancer risk in postmenopausal women

In a recent study published in eBioMedicine, researchers determine the genetic regulation of blood estrone levels in postmenopausal women to explore associations between their genetic loci and endometrial cancer.

Study: Genome-wide association study identifies genetic regulation of oestrone concentrations and association with endometrial cancer risk in postmenopausal women. Image Credit: Peakstock / Shutterstock.com

The role of estrogens in endometrial cancer

Once a woman has gone through menopause, her ovaries no longer produce estrogens, thereby causing her serum estradiol concentrations to be extremely low or undetectable. In Type 1 estrogen-sensitive endometrial cancer, which accounts for over 80% of all endometrial cancers and predominantly affects menopausal women, estrone, the contributing estrogen, is synthesized in non-ovarian tissues like fat. Following the production of estrone in these tissues, this hormone is converted into estradiol, a more potent form of estrogen.

Previous studies have shown that obesity is a significant risk factor for Type 1 endometrial cancer. This association may be attributed to the greater amount of total fat mass that facilitates more estrone production.

Alternatively, various genetic factors may lead to increased estrone production after menopause, thereby contributing to an increased risk of endometrial cancer in these women. In fact, one variant in the CYP19A1 gene, which is involved in the aromatization of testosterone to estradiol, has been positively associated with estradiol concentrations and postmenopausal endometrial cancer.

Importantly, studies investigating the relationship between CYP19A1 variants and endometrial cancer risk have been limited due to their small sample size and lack of sensitive analytical methods.

About the study

In the present genome-wide association study (GWAS), researchers quantified blood estrone, testosterone, and dehydroepiandrosterone (DHEA) levels with high precision using liquid chromatography-tandem mass spectrometry (LCMS) to identify single nucleotide polymorphisms (SNPs) associated with sex hormone concentrations. The association between hormone-associated SNPs and endometrial cancer was determined from 205,427 white British females between 39 and 71 years of age, 0.9% of whom were diagnosed with endometrial cancer.

The study also included women 70 and older from the Sex Hormones in Older Women (SHOW) and ASPirin in Reducing Events in the Elderly (ASPREE) studies. Non-fasting blood samples were obtained from these study participants to measure sex hormone concentrations through LCMS.

Study findings

The final analysis cohort comprised 4,951 postmenopausal women of European descent, with a median age of 73.9. No genome-wide signals were observed for testosterone or DHEA, the latter of which is the precursor for both estrone and testosterone. However, the GWAS identified four independent SNPs for estrone concentrations below the genome-wide significance threshold after adjusting for age and BMI.

These SNPs included rs34670419, which may be involved in transcriptional regulation; rs56400819, which contributes to the DNA damage response; rs2846729, which is mapped to a ribonucleic acid (RNA) gene; and rs2414098, which is mapped to CYP19A1. The SNP with the highest prevalence within this study cohort was rs56400819 at 45% as compared to rs34670419, which had the lowest prevalence in this cohort at 4%.  

Lower estrone levels were observed for rs34670419, rs2846729, and rs2414098 carriers compared to rs56400819 carriers, who exhibited higher estrone concentrations. Furthermore, rs2414098 carriers had a significantly lower risk of endometrial cancer after adjusting for age at recruitment, BMI, parity, and history of diabetes.

Conclusions

Previous GWAS on endometrial cancer have primarily focused on estradiol concentrations; however, this hormone often cannot be accurately quantified, particularly among postmenopausal women. Comparatively, the current study examined estrone concentrations, in which a dose-response relationship was observed between the identified SNPs and estrone concentrations.

Importantly, the researchers of the current study limited one of their analyses on rs2414098 to women over 58 years of age in an effort to ensure postmenopausal status. These findings confirm that the impact of this SNP on cancer risk can be attributed to estrone and is independent of the effects of circulating estrogens and progesterone.

The current study highlights the importance of measuring estrone levels, in addition to other sex hormones, in postmenopausal women to determine cancer risk. Some important strengths of this study include the confirmation of postmenopausal women in the study cohort, the large sample size, and the use of LCMS, a highly sensitive and precise analytical instrument.