BRCA1/2 mutations may alter endometrial, ovarian function

By Lynda Williams, Senior medwireNews Reporter

Scientists have detected significant differences in endometrial thickness and hormone levels in women with and without BRCA1/2 mutations that may play a role in cancer susceptibility or development.

“Our findings suggest that BRCA1/2 germline mutations are driving carcinogenesis only in part via altered molecular pathways (eg, those involved in DNA repair) in the organ at risk, and that BRCA1/2-associated changes in the endocrine system are additional factors,” write Martin Widschwendter (University College London, UK) and co-authors.

“These insights could act as a major impetus for novel chemoprevention trials using strategies that can exploit the hormonal dysregulation in carriers of BRCA1/2 mutations,” they suggest in The Lancet Oncology.

The researchers analyzed ultrasound data from the UK Familial Ovarian Cancer Screening Study for 228 women with the BRCA1 or BRCA2 mutations and 754 women without, focusing on the follicular phase (days 10–14) and luteal phase (days 21–26) of the menstrual cycle.

After adjusting for age and menstrual cycle day, follicular phase endometrial thickness was significantly greater in BRCA1/2 carriers than controls (odds ratio [OR]=1.11), while luteal phase endometrial thickness was significantly lower (OR=0.90).

Premenopausal estradiol and progesterone levels were also determined in 70 samples from 59 mutation carriers and 339 samples from 283 controls. During the luteal phase, median progesterone titers were a significant 121% higher, and estradiol titers a significant 33% higher, in BRCA1/2 carriers than controls.

This means that 59% of women with a BRCA1/2 mutation had serum progesterone concentrations in the top quartile for the women without a mutation, the team says. The results were not explained by differences in use of oral contraceptives between the patient groups.

“[O]ur findings provide novel insights into the high penetrance for breast cancer (via higher progesterone and oestrogen titres) and also possibly ovarian cancer (via higher oestrogen titres and potentially lower titres of anti-Müllerian hormone) in carriers of BRCA1/BRCA2 mutations,” Widschwendter et al comment.

In an accompanying comment, however, Martha Hickey (University of Melbourne, Victoria, Australia) says it is “unclear” why the BRCA1/2 DNA repair genes should affect ovarian sex steroid production.

In addition, she notes that higher levels of circulating estradiol but not progesterone have previously been linked to premenopausal breast cancer risk.

“The complex relation between gene mutations, ovarian cancer risk, endocrine function, endocrine production, and receptivity in BRCA1/2 mutation carriers still need to be established,” Hickey writes.

“These provocative findings might open a new direction in mechanistic studies that increase understanding of cancer mechanisms in high-risk women.”

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