Linking Estrone Levels and Endometrial Cancer in Postmenopausal Women

A groundbreaking study published in eBioMedicine has shed light on the genetic regulation of blood estrone levels in postmenopausal women and its association with endometrial cancer. This research offers significant insights into the complexities of hormonal changes and cancer risks in postmenopausal women.

The Role of Estrogens in Endometrial Cancer

Postmenopausal women experience a drop in estrogen production, particularly estradiol, due to the cessation of ovarian function. However, estrone, another form of estrogen, continues to be synthesized in non-ovarian tissues like fat. This is particularly relevant in Type 1 endometrial cancer, which is sensitive to estrogens and common among menopausal women.

Obesity has been recognized as a key risk factor for Type 1 endometrial cancer, likely due to the increased estrone production in greater fat mass.

Genetic Factors Influencing Estrone Production

The study highlights the potential of genetic factors in increasing estrone production post-menopause, contributing to a heightened risk of endometrial cancer. Specifically, a variant in the CYP19A1 gene, involved in converting testosterone to estradiol, is linked to higher estradiol levels and endometrial cancer risk in postmenopausal women.

Insights from the Genome-Wide Association Study (GWAS)

The study utilized a GWAS approach, analyzing blood samples from over 200,000 white British females aged 39-71 using liquid chromatography-tandem mass spectrometry (LCMS) to identify single nucleotide polymorphisms (SNPs) associated with hormone levels.

Key Findings:

• No Significant Signals for Testosterone or DHEA: DHEA, a precursor for both estrone and testosterone, did not show significant genome-wide signals.

• Identification of Four Independent SNPs for Estrone: These include rs34670419, rs56400819, rs2846729, and rs2414098, with rs56400819 being the most prevalent in the study cohort.

Implications:

• Variations in Estrone Levels: The study found that carriers of different SNPs exhibited varying estrone levels.

• Link to Endometrial Cancer Risk: Particularly, rs2414098 carriers showed a significantly lower risk of endometrial cancer, emphasizing the genetic influence on hormone-related cancer risks.

Conclusions

The study marks a significant advancement in understanding the hormonal dynamics in postmenopausal women. By focusing on estrone, which is often more prevalent than estradiol in postmenopausal women, the research provides a clearer picture of the hormonal landscape influencing endometrial cancer risk.