Serum Vitamin D, Genetic Polymorphisms & Ovarian Cancer

描述(由申请人提供)： 最近的实验数据显示，除了在矿物质和骨骼代谢中众所周知的作用外，维生素D还参与调节一系列正常和恶性细胞的生长、分化和功能。维生素D特异性受体存在于正常哺乳动物卵巢、人类卵巢组织和卵巢癌细胞系中。给予活性维生素D化合物与卵巢细胞的促分化和抗增殖改变、诱导细胞凋亡、调节生长因子信号转导以及抑制侵袭和转移有关。 目前的应用建议检验这一假设，即维生素D可能是支持卵巢细胞分化/抗增殖表型所必需的，而维生素D缺乏(由于血清中活性维生素D化合物水平低和/或由于维生素D受体基因多态性)与卵巢癌风险增加有关。 这项应用的主要特殊目的是进行第一次分析性研究，以检测血清中25-羟基维生素D3的水平，作为卵巢癌风险的生物标志物。第二个特异性目的是评估功能性维生素D受体基因(Taq1、BsmI、ApaI、PolyA微卫星)在卵巢癌中的可能作用。 拟议的嵌套病例对照研究基于两个现有的前瞻性队列：纽约大学妇女健康研究(NYUWHS)和瑞典北部健康和疾病研究(NSHDS)。除了有价值的生物标本来源，包括血清和DNA样本外，NYUWHS和NSHDS还提供了既定的后续机制。至少有136例卵巢癌病例可用于这项研究(80例来自NYUWHS，56例来自NSHDS)，以及272名单独匹配的对照组。 证实维生素D作为卵巢癌风险的潜在生物标志物的作用将具有直接的临床意义：1)血清维生素D水平和/或维生素D受体基因多态性可用于识别卵巢癌风险增加的妇女，目前缺乏可靠的生物标志物用于筛查和早期检测；2)干预钙动员活性有限的维生素D类似物可能是一种潜在的卵巢癌化学预防的新治疗方法。

DESCRIPTION (provided by applicant): Recent experimental data revealed that in addition to its well-known role in mineral and skeletal metabolism, vitamin D is involved in the regulation of growth, differentiation and function of a wide range of normal and malignant cells. Vitamin D-specific receptors are present in normal mammalian ovaries, in human ovarian tissues and in the ovarian carcinoma cell lines. Administration of active vitamin D compounds had been associated with a considerable prodifferentiation and antiproliferative changes in ovarian cells, induction of apoptosis, modulation of growth factor signaling and inhibition of invasion and metastasis. The current application proposes to test the hypothesis that vitamin D may be essential in supporting the differentiated/antiproliferative phenotype of ovarian cells, whereas hypovitaminosis D (due to low serum levels of active vitamin D compounds and/or due to vitamin D receptor gene polymorphisms) is associated with an increased risk of ovarian cancer. The primary specific aim of this application is to conduct the first analytical study to examine serum levels of 25-hydroxyvitamin-D3, an active form of vitamin D, as biomarker of ovarian cancer risk. The secondary specific aim is to assess the possible role of functional vitamin D receptor gene polymorphisms (Taql, BsmI, ApaI, poly-A microsatellite) in ovarian cancer. The proposed nested case-control study is based on two existing prospective cohorts: the New York University Women's Health Study (NYUWHS) and the Northern Sweden Health and Disease Study (NSHDS). Besides the valuable source of biological specimens, which include serum and DNA samples, NYUWHS and NSHDS provide the established mechanisms of follow-up. At least 136 cases of ovarian cancer are available for the study (80 cases from the NYUWHS and 56 cases from the NSHDS), as well as 272 individually-matched controls. Demonstration of the role of vitamin D as a potential biomarker of ovarian cancer risk would have a direct clinical implications: 1) serum levels of vitamin D and/or vitamin D receptor polymorphisms could be used to identify women at increased risk of ovarian cancer, which is currently characterized by lack of reliable biomarkers for screening and early detection; 2) an intervention with vitamin D analogues with limited calcium mobilizing activity could be a potentially new therapeutic approach for primary chemoprevention of ovarian cancer.