Variants of genes that reduce the function of the progesterone receptor, vitamin D receptor, and 1[alpha]-hydroxylase enzyme are associated with an earlier onset of breast cancer

Alisa Dymova; Tatyana Shkeleva; Svetlana Kalinchenko; Marina Zhilenko; Svetlana Samoylova

doi:10.1530/endoabs.99.P509

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Endocrine Abstracts (2024) 99 P509 | DOI: 10.1530/endoabs.99.P509

ECE2024 Poster Presentations Endocrine-Related Cancer (40 abstracts)

Variants of genes that reduce the function of the progesterone receptor, vitamin D receptor, and 1α-hydroxylase enzyme are associated with an earlier onset of breast cancer

Alisa Dymova ¹ , Tatyana Shkeleva ² , Svetlana Kalinchenko ³ , Marina Zhilenko ⁴ & Svetlana Samoylova ⁵

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¹Moscow, Gynecology department, Moscow, Russian Federation; ², Moscow; ³Peoples’ Friendship University of Russia - RUDN University, Clinic prof. Kalinchenko, Moscow, Russian Federation; ⁴, gynecology department, Moscow, Russian Federation; ⁵First Moscow State Medical University, Department of Oncology, Radiotherapy and Plastic Surgery, Russian Federation

Background: Previous studies have investigated the association between genetic variability in the progesterone receptor gene and various hormonally-related conditions, such as breast cancer (BC), endometrial and ovarian cancers. Vitamin D deficiency can also lead to oncological conditions, including BC. Progesterone and Vitamin D induce their hormonal effects on target cells by binding the active form of the hormone to its receptors. Therefore, any genetic variations that may cause the dissociation of progesterone and vitamin D receptors, as well as a reduction in the synthesis of the active hormone form, may lead to increased susceptibility to BC. Notably, earlier studies did not take into account the morphological characteristics of tumors and the influence of molecular-genetic features on the age of disease manifestation.

Objective: This study aimed to assess the association between functional-reducing variants in the PGR, VDR, and CYP27B1 genes with the risk of hormone-dependent breast cancer (HBC) and the age of disease manifestation.

Methods: A retrospective case-control study was conducted, involving 87 women aged 40–72 years. Of these, 42 women had a diagnosis of HBC, and 45 women had no history of HBC in their personal or familial medical records. Genotyping was performed using SNP genotyping methods through direct sequencing. Functional-reducing variants in the progesterone receptor gene PGR c.1486G>T; p.Val660Leu, vitamin D receptor BsmI Polymorphism IVS10+283G>A, and 1α-hydroxylase enzyme g.57764205A>G; c.1137-29T>C were investigated.

Results: A significantly higher frequency of the minor allele of PGR (45% vs 16%), VDR (29% vs 17%), and the functional-reducing allele of the CYP27B1 enzyme (43% vs 12%) was observed among patients with HBC compared to the control group, confirming the association of these genetic variants with the risk of developing HBC. A significant association of PGR and VDR genotypes with HBC was observed in younger patients up to 55 years old. In older patients, the frequency of PGR and VDR variants decreased and approached the control group, indicating the contribution of other factors to the pathogenesis of the disease after the age of 55.

Conclusions: This report confirms the contribution of PGR, VDR, and CYP27B1 gene variants to the etiology of BC. The low sensitivity of PGR and VDR receptors is associated with earlier forms of HBC. Genotyping of vitamin D receptors (VDR), the activity of the 1-α-hydroxylase enzyme (CYP27B1), and progesterone receptors (PGR) in the future will enable the development of a screening strategy for identifying women at risk of developing HBC.