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

维生素D缺乏或循环维生素D水平低与癌症（包括乳腺癌（BC））风险增加的相关性已受到广泛关注。实验研究表明，维生素D具有许多抗癌特性，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预后和生存结果的作用较少受到关注。研究表明，循环维生素D和调节维生素D代谢和信号传导的基因多态性都与BC风险相关，然而，我们对BC预后的相关性知之甚少。一些研究将低循环维生素D水平与BC结果的预后因素联系起来，例如晚期疾病或转移。只有一项研究直接评估了维生素D状态和BC生存率之间的关联，没有研究调查了维生素D多态性与这种关联。本研究拟在中国女性乳腺癌前瞻性队列研究中探讨这些问题，并验证三个假设：1）循环维生素D水平可预测乳腺癌进展和预后2）维生素D代谢和信号传导途径基因中的遗传多态性影响BC幸存者中的循环维生素D水平及其生物利用度;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。该研究将使用上海乳腺癌生存研究（SBCSS）和上海乳腺癌全基因组关联研究（GWAS）的资源。我们将纳入2，073名新诊断为侵袭性BC的女性，诊断时年龄为20-74岁，他们有血液样本用于评估循环25（OH）D和基因型信息。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和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途径基因多态性对BC进展和预后的联合作用。孟德尔随机化（MR）方法将用于重新评估这种关联。乳腺癌生存率被认为是癌症相关公共卫生计划的重要组成部分。这项研究旨在通过评估循环维生素D和维生素D通路基因多态性与乳腺癌预后的关系来填补我们知识的空白。这项研究将扩大我们对“维生素D状态”和相关通路基因多态性在BC预后中的作用的理解。研究结果可能会导致新的预防和治疗策略的发展，可应用于BC患者。此外，这项研究可以帮助确定是否应该考虑对疾病进展高风险的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.