A Pooled Analysis of 25-hydroxyvitamin D and Colorectal Cancer Survival

描述(申请人提供)：尽管在预防、筛查、早期发现和治疗方面取得了进展，但结直肠癌(CRC)仍然是美国第三大最常见的癌症诊断和第二大癌症死亡原因，预计2013年将有大约142,820例新病例和50,830例死亡。虽然早期发现和治疗结直肠癌的进展已经导致了相对较长的生存时间，但可能有助于生存的可改变的饮食和生活方式因素的影响还没有得到充分的探讨。维生素D是一种潜在的化学预防结直肠癌患者癌症进展、复发和死亡的药物，其机制可能与其直接影响细胞周期、调节生长因子信号、雌激素和雄激素受体通路、炎症、氧化应激和免疫功能以及抑制侵袭、转移和血管生成有关。循环中较高的维生素D水平一直与较低的结直肠癌风险相关，但它们与结直肠癌存活率的关系相对未被探讨。基于基础科学和有限的人类证据，我们假设，较高水平的前瞻性收集、诊断前循环中的维生素D[25(OH)D，维生素D状况的最佳指标]与较低的结直肠癌特异性和总体死亡率有关。我们将在正在进行的NCI资助的(R01 CA152071)乳腺癌和结直肠癌维生素D池项目(VDPP)的一项辅助研究中对此进行研究，该项目汇集了来自美国、欧洲和亚洲的21项前瞻性队列研究的综合原始数据，以调查25(OH)D水平与这些癌症部位总体风险之间的关系，按肿瘤亚型和由个人特征、生活方式因素、维生素D受体(VDR)多态和其他生物标记物定义的人群亚组来确定。在美国、欧洲和亚洲进行的16项队列研究中，我们将分析(使用传统的和竞争性的风险生存分析)诊断前的25(OH)D水平与5,795例结直肠癌病例(其中有2,627例死亡)的结直肠癌特异性和总体死亡率之间的关系。作为父母资助的一部分，25(OH)D水平已被校准到一个共同的标准实验室，以便不仅使用研究特定的五分位数，而且还使用整个联盟范围的五分位数和共同的绝对切入点来对25(OH)D水平进行分类。这项辅助研究提供了一个独特的、具有成本效益和资源效率的机会，这是目前可用的最大规模的汇集研究，以调查诊断前25(OH)D水平与结直肠癌特异性和总体死亡率之间的关系，特别强调潜在的生活方式(体重指数、体力活动、钙摄入量)和遗传(VDR的变异)。 队列的一个子集)效应修饰物，并通过结肠亚部位、性别和肿瘤特征来检查维生素D对结直肠癌生存率的影响。这项研究将在了解维生素D是否影响CRC的进展和生存方面向前迈出重要的一步，并深入了解这种重要化合物在CRC治疗方案中的潜在应用。

DESCRIPTION (provided by applicant): Despite advances in prevention, screening, early detection, and treatment, colorectal cancer (CRC) remains the 3rd most commonly diagnosed cancer and the 2nd leading cause of cancer death in the US, with approximately 142,820 new cases and 50,830 deaths expected in 2013. Although advances in CRC early detection and treatment have resulted in relatively longer survival, the impact of modifiable dietary and lifestye factors that may contribute to survival has not been sufficiently explored. Vitamin D is a potentia agent for the chemoprevention of cancer progression, recurrence and death in CRC patients, possibly through mechanisms related to its direct effects on the cell cycle, modulation of growth factor signaling, estrogen and androgen receptor pathways, inflammation, oxidative stress, and immune function, as well as inhibition of invasion, metastasis, and angiogenesis. Higher circulating vitamin D levels are consistently associated with lower risk for CRC, but their association with CRC survival is relatively unexplored. Based on basic science and limited human evidence, we hypothesize that higher levels of prospectively collected, pre-diagnostic circulating vitamin D [25(OH)D, the best indicator of vitamin D status] are associated with lower CRC-specific and overall mortality among CRC cases. We will investigate this in an adjunct study to the ongoing, NCI-funded (R01 CA152071) Vitamin D Pooling Project of Breast and Colorectal Cancer (VDPP), which pools comprehensive primary data from 21 prospective cohort studies from the US, Europe, and Asia to investigate associations between 25(OH)D levels and risk of these cancer sites overall, by tumor subtype, and by population subgroups defined by personal characteristics, lifestyle factors, vitamin D receptor (VDR) polymorphisms, and other biomarkers. We will analyze (using traditional and competing risk survival analyses) the association between pre-diagnostic 25(OH) D levels and risk of CRC-specific and overall mortality in 5,795 CRC cases (among which there were 2,627 deaths) in 16 cohort studies conducted in the US, Europe, and Asia. As part of the parent grant, the 25(OH) D levels have been calibrated to a common standard laboratory to enable categorization of 25(OH)D levels using not only study-specific quintiles, but also consortium-wide quintiles and common absolute cut points. This adjunct study offers a unique, cost-effective and resource-efficient opportunity i the largest pooled study currently available to investigate an association between pre-diagnostic 25(OH)D levels and CRC-specific and overall mortality, with particular emphasis on potential lifestyle (body mass index, physical activity, calcium intake) and genetic (variation in the VDR in a sub-set of cohorts) effect modifiers, and examine the effects of vitamin D on CRC survival by colon sub-site, sex, and tumor characteristics. This study will provide an important step forward in understanding whether vitamin D affects CRC progression and survival, as well as insight into the potential application of this important compound in CRC treatment regimens.