Plasma Lipid Markers and Cancer Risk

描述(申请人提供)：在这项申请中，我们将利用28,345名女性健康研究(WHS)参与者的现有血脂标志物数据，对标准脂标记物(总胆固醇、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、甘油三酯)和新型脂标记物(载脂蛋白A-1(ApoA-1)和载脂蛋白B100)，以及长期使用他汀类药物与总浸润性癌、乳腺癌、结直肠癌和子宫内膜癌风险的关系进行详细的前瞻性队列评估。血脂可能通过与胰岛素抵抗、炎症和氧化应激相关而影响癌症风险。他汀类药物具有抗炎、促凋亡和抗增殖作用，这可能使它们与癌症预防有关。此外，我们将根据影响血脂水平的因素(例如绝经状态、体重指数、体力活动、绝经后激素使用、酒精摄入量和其他与肥胖有关的血浆标记物)以及肿瘤特征(例如雌激素受体状态)来评估这些相关性。我们还将通过进行一项排除前两年随访的分析来解决临床前疾病可能改变血脂水平的问题。到2011年6月，平均随访时间为17年，我们预计有3,506例确诊的浸润性癌症，包括1,473例乳腺癌、338例结直肠癌和28,345名提供基线血样且在基线水平没有癌症和心血管疾病的女性的304例子宫内膜癌。已经在这28,345份血液样本中测量了标准和新的血脂标志物。因此，这项拟议的研究提供了一个独特和非同寻常的机会来进行前瞻性队列分析的血脂标记物和癌症的风险。这项拟议的研究是创新的，因为在前瞻性研究中，血浆载脂蛋白A-1和载脂蛋白B100与癌症风险之间的关系在很大程度上是未被探索的。很少有研究检验血脂标记物和长期服用他汀类药物与子宫内膜癌风险的关系。这项拟议的研究将首次评估血浆载脂蛋白A-1和载脂蛋白B100与总体癌症风险的关系，以及载脂蛋白B100与子宫内膜癌风险的关系，以及首次对载脂蛋白A-I与乳腺癌和子宫内膜癌的风险进行前瞻性评估。这项研究还有许多其他优势，包括前瞻性队列研究设计、大样本量(n=28,345)、大量病例(n=3,506)、长期随访(17年)、良好的环境、其他血浆肥胖相关标记物的可用性、关于协变量和肿瘤特征的详细信息。正在进行的WHS提供对癌症病例的跟踪、确定和记录，以及关于生物标记物、他汀类药物使用和协变量的数据。因此，这项拟议的研究提供了一个独特的机会，以异常经济高效的方式测试关于癌症风险的有希望的假说。这项研究的发现将有助于阐明血脂标记物在识别女性在 谁将从化学预防或增加筛查中受益最大，以及长期使用他汀类药物在癌症化学预防中的作用，谁就是癌症的高风险人群。 与公众健康的相关性：拟议的研究将对总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和甘油三酯等标准脂类标记物以及载脂蛋白A-1和B100的新脂类标记物进行全面、前瞻性的队列评估，以及长期使用他汀类药物与总浸润性癌症以及乳腺癌、结直肠癌和子宫内膜癌风险的关系。这项研究的结果将有助于阐明血脂标记物在确定癌症高危女性谁将从化学预防或增加筛查中受益最大方面的作用，以及长期使用他汀类药物在癌症化学预防中的作用。

DESCRIPTION (provided by applicant): In this application, we will take advantage of the existing data of plasma lipid markers in 28,345 Women's Health Study (WHS) participants and conduct a detailed, prospective cohort evaluation of standard lipid markers (total cholesterol, low-density lipoprotein cholesterol (LDL-C), HDL-C, triglycerides), and novel lipid markers (apolipoprotein A-1 (Apo A-1) and Apo B100), as well as long-term use of statins in relation to risk of total invasive cancer and breast, colorectal and endometrial cancer. Blood lipids may affect cancer risk through their association with insulin resistance, inflammation and oxidative stress. Statins have anti- inflammatory, proapoptotic, and antiproliferative effects, which may make them relevant to cancer prevention. Also, we will evaluate these associations by factors that affect plasma lipid levels (e.g., menopausal status, body mass index, physical activity, postmenopausal hormone use, alcohol intake, and other plasma obesity- related markers), as well as by tumor characteristics (e.g., estrogen receptor status). We will also address the issue that the preclinical disease may alter blood lipid levels by conducting an analysis of excluding the first 2 years of follow-up. By June 2011, with a mean follow-up duration of 17 years, we expect 3,506 confirmed incident invasive cancers, including 1,473 breast cancers, 338 colorectal cancers, and 304 endometrial cancers in 28,345 women who provided a baseline blood sample and were free of cancer and cardiovascular disease at baseline. Standard and novel lipid markers were already measured in these 28,345 blood samples. Thus, this proposed study affords a unique and extraordinary opportunity to conduct a prospective cohort analysis of plasma lipid markers and cancer risk. This proposed study is innovative as the associations between plasma Apo A-1 and Apo B100 and cancer risk are largely unexplored in prospective studies. Few studies have examined blood lipid markers and long-term statin use in relation to endometrial cancer risk. This proposed study will be the first evaluation of the relations between plasma Apo A-1 and Apo B100 and overall cancer risk and between Apo B100 and endometrial cancer risk, as well as the first prospective evaluation of Apo A-I and risk of breast and endometrial cancer. This study also has numerous other strengths, including the prospective cohort study design, large sample size (n = 28,345), large numbers of cases (n = 3,506), long duration of follow-up (17 years), excellent environment, availability of other plasma obesity-related markers, detailed information on covariates and tumor characteristics. The ongoing WHS provides follow-up, ascertainment and documentation of cancer cases, and data on biomarkers, statin use, and covariates. Thus, this proposed study affords a unique opportunity to test promising hypotheses about cancer risk in an exceptionally cost-efficient manner. Findings from this study will help clarify the role of plasma lipid markers in identifying women at high risk of cancer who would most benefit from chemoprevention or increased screening and the role of long-term use of statins in cancer chemoprevention. PUBLIC HEALTH RELEVANCE: The proposed study will conduct a comprehensive, prospective cohort evaluation of standard lipid markers of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, and novel lipid markers of apolipoproteins A-1 and B100 , as well as long-term use of statins in relation to risk of total invasive cancer and breast, colorectal and endometrial cancer in the Women's Health Study. Findings from this study will help clarify the role of plasma lipid markers in identifying women at high risk of cancer who would most benefit from chemoprevention or increased screening and the role of long-term use of statins in cancer chemoprevention.