Vitamin D status, Gene Polymorphism and Breast Cancer Progression/Prognosis

描述(由申请者提供)：项目摘要/摘要)维生素D缺乏或循环中维生素D水平低与包括乳腺癌(BC)在内的癌症风险增加之间的关系已受到广泛关注。实验研究表明，维生素D具有多种抗癌作用，包括抗增殖、抗血管生成、促凋亡和免疫调节作用。维生素D缺乏对BC预后和生存结局的影响尚未引起足够的重视。研究表明，循环中的维生素D和调节维生素D代谢和信号转导的基因多态性都与BC风险有关，然而，我们对BC预后的相关性了解较少。少数研究已经将循环中低维生素D水平与BC预后的预后因素联系起来，如晚期疾病或转移。只有一项研究直接评估了维生素D状态和BC存活率之间的关联，没有研究调查这种关联与维生素D基因多态的关系。我们建议在中国女性BC患者的前瞻性队列中解决这些问题，并检验三个假设：1)循环维生素D水平将预测BC的进展和癌症治疗后的预后(复发、转移、整体或疾病特异性死亡)；2)维生素D代谢和信号通路基因的基因多态性影响BC幸存者的循环维生素D水平及其生物利用度；以及3)循环维生素D和维生素D基因多态性共同影响BC的进展和预后。这项拟议的研究将使用来自上海乳腺癌生存研究(SBCS)和上海乳腺癌基因组范围协会研究(GWAS)的资源。我们将包括2,073名新诊断为侵袭性BC的女性，诊断时年龄为20-74岁，她们既有用于评估循环25(OH)D的血液样本，也有基因信息。有关癌症诊断和常规治疗、乳腺癌复发和死亡原因的信息将通过病历审查进行核实。我们将使用适当的统计方法，并控制已知的预后因素，评估循环维生素D水平及其与维生素D途径基因多态性的联合作用对BC进展和预后的影响。孟德尔随机化(MR)方法将被用来重新评估这种联系。乳腺癌的存活率被认为是癌症相关公共卫生计划的关键组成部分。这项拟议的研究旨在通过评估循环维生素D和维生素D途径基因多态与乳腺癌预后的关系来填补我们知识的空白。本研究将加深我们对维生素D状态及其相关途径基因多态性在BC预后中的作用的理解。这一研究结果可能会导致新的预防和治疗策略的开发，这些策略可以应用于BC患者。此外，这项研究可能有助于确定是否应该考虑对疾病进展风险较高的BC患者进行维生素D的化学预防临床试验。

DESCRIPTION (provided by applicant): Project Summary/Abstract) The association of vitamin D deficiency, or low levels of circulating vitamin D, with increased risk for cancers, including breast cancer (BC), has received extensive attention. Experimental studies have shown that vitamin D has many anti-cancer properties, including anti-proliferative, anti-angiogenic, pro-apoptotic, and immunomodulation effects. Less attention has been paid to the role of vitamin D deficiency on BC prognosis and survival outcomes. Studies have shown that circulating vitamin D and polymorphisms in genes regulating vitamin D metabolism and signaling are both associated with BC risk, however, we know less about associations with BC prognosis. A few studies have linked low circulating vitamin D levels with prognostic factors for BC outcome, such as advanced disease or metastasis. Only one study directly evaluated the association between vitamin D status and BC survival, and no study has investigated this association in relation to vitamin D polymorphisms. We propose to address these questions in a prospective cohort of Chinese women with BC and test three hypotheses: 1) Circulating vitamin D level will predict BC progression and prognosis (recurrence, metastasis, overall or disease-specific death) after cancer treatment; 2) Genetic polymorphisms in vitamin D metabolism and signaling pathway genes affect circulating vitamin D level and its bioavailability in BC survivors; and 3) Circulating vitamin D and vitamin D gene polymorphisms together affect BC progression and prognosis. The proposed study will use resources from the Shanghai Breast Cancer Survival Study (SBCSS) and the Shanghai Breast Cancer Genome-Wide Association Study (GWAS). We will include 2,073 women newly-diagnosed with invasive BC and aged 20-74 years at the time of diagnosis, who have both blood samples for assessing circulating 25(OH)D and genotype information. Information on cancer diagnosis and conventional treatment, breast cancer recurrence, and causes of death will be verified through medical chart reviews. We will evaluate the effect of circulating vitamin D level and its combined effect with polymorphisms in the vitamin D pathway genes on BC progression and prognosis using appropriate statistical methods and controlling for known prognostic factors. The Mendelian Randomization (MR) method will be used to re-assess this association. Breast cancer survivorship is recognized as a critical component of cancer- related public health programs. The proposed study aims to fill a gap in our knowledge by evaluating the associations of circulating vitamin D and vitamin D pathway gene polymorphisms with breast cancer prognosis. This study will expand our understanding of the role of "Vitamin D status" and related pathway gene polymorphisms in BC prognosis. The study results could potentially lead to the development of new preventive and therapeutic strategies that can be applied to BC patients. In addition, the research could help determine if chemoprevention clinical trials with vitamin D should be considered for BC patients at high-risk for disease progression.