Premature ovarian aging in BRCA carriers: a prototype of systemic precocious aging?
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Irit Ben-Aharon1,5,*, Mattan Levi2,*, David Margel1,5, Rinat Yerushalmi1,5, Shulamith Rizel1, Shlomit Perry1,5, Eran Sharon3,5, Noa Hasky2, Ronit Abir4,5, Benny Fisch4,5, Ana Tobar6, Ruth Shalgi2 and Salomon Marcello Stemmer1,5
1Institute of Oncology, Davidoff Center, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel
2Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Tel-Aviv, Israel
3Department of Surgery, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel
4IVF and Infertility Unit, Schneider Women Hospital, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel
5Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Tel-Aviv, Israel
6Department of Pathology, Rabin Medical Center, Petach Tikva, Israel
*These authors have contributed equally to this work
Irit Ben-Aharon, email: [email protected]
Keywords: BRCA; ovarian aging; systemic precocious aging
Received: December 01, 2017 Accepted: February 27, 2018 Published: March 23, 2018
Purpose: Though former evidence implies a correlation of breast cancer susceptibility gene (BRCA) mutation with reduced ovarian reserve, the data is yet inconsistent. Our aim was to investigate biomarkers of ovarian aging in a cohort of young healthy carriers of the BRCA mutation. We hypothesized that the role played by BRCA genes in aging pathways is not exclusive to the ovary.
Experimental Design: Healthy female BRCA carriers, 40 years or younger and healthy male BRCA carriers, 50 years or younger, were enrolled in the study. Serum anti-mullerian Hormone (AMH), fibroblast growth factor-23 (FGF-23), Klotho and IL-1 were measured by enzyme-linked immunosorbent assay (ELISA). Ovarian AMH and protein kinase B (AKT) mRNA from BRCA carriers who underwent prophylactic oophorectomy and from age-matched, healthy, non-carriers who underwent partial oophorectomy due to benign conditions were analyzed by qPCR.
Results: Thirty-three female (median age 35y) and 20 male (44y) BRCA carriers were enrolled into the study and matched to control non-carriers (34y and 43y, respectively). Serum AMH level was significantly lower in BRCA female carriers than in both non-carrier controls and age-matched nomograms. The levels of ovarian AMH and AKT mRNA were significantly lower in carriers than in controls. The systemic aging cytokines FGF-23, klotho and IL-1 displayed a differential expression in carriers of both genders. FGF-23 level was higher in carriers (P=0.06).
Conclusions: Our results suggest a link between BRCA mutation, accelerated ovarian aging and systemic aging-related pathophysiology.
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