Premature ovarian aging in BRCA carriers: a prototype of systemic precocious aging?
Premature ovarian aging in BRCA carriers: a prototype of systemic precocious aging?
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DOI：
10.18632/oncotarget.24638
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发表时间：
2018-03-23
期刊：
影响因子：
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通讯作者：
Stemmer SM
中科院分区：
文献类型：
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作者：
Ben-Aharon I;Levi M;Margel D;Yerushalmi R;Rizel S;Perry S;Sharon E;Hasky N;Abir R;Fisch B;Tobar A;Shalgi R;Stemmer SM
尽管以前的证据表明乳腺癌易感基因(BRCA)突变与卵巢储备减少有关，但数据仍不一致。我们的目的是研究BRCA突变的年轻健康携带者队列中卵巢老化的生物标志物。我们假设BRCA基因在衰老途径中扮演的角色并不是卵巢所独有的。健康的女性BRCA携带者、40岁及以下的健康男性BRCA携带者、50岁或以下的健康男性BRCA携带者参加了研究。采用酶联免疫吸附试验(ELISA)检测血清抗苗勒氏激素(AMH)、成纤维细胞生长因子-23(FGF-23)、Klotho和IL-1水平。对预防性卵巢切除的BRCA携带者和因良性疾病行卵巢部分切除术的年龄匹配的健康非BRCA携带者的卵巢AMH和蛋白激酶B(AKT)基因进行定量聚合酶链式反应(QPCR)分析。33名女性(中位年龄35岁)和20名男性(44岁)BRCA携带者进入研究，并与非携带者(分别为34岁和43岁)进行匹配。BRCA女性携带者的血清AMH水平显著低于非携带者对照组和年龄匹配的正常对照。携带者的卵巢AMH和AKT mRNA水平显著低于对照组。全身性衰老细胞因子FGF-23、Klotho和IL-1在男女携带者中的表达存在差异。成纤维细胞生长因子-23在携带者中水平较高(P=0.06)。我们的结果提示BRCA突变、卵巢老化加速和全身衰老相关的病理生理学之间存在联系。
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. 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. 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). Our results suggest a link between BRCA mutation, accelerated ovarian aging and systemic aging-related pathophysiology.