Breast Cancer Survival: Lifestyle and Genetic Determinants

描述(申请人提供)：在乳腺癌中幸存下来的女性人数正在迅速上升。尽管最初的治疗取得了成功，但许多患者仍在与疾病复发和过早死亡的恐惧作斗争。然而，非临床因素，特别是遗传因素对乳腺癌预后的影响在很大程度上是未知的。这项拟议的研究将利用对3593名乳腺癌患者进行的两项成熟的队列研究的现有资源，来综合评估以下假设：1)乳腺癌的生存可能与编码血管生成因子和基质金属蛋白酶的基因的遗传多态有关，这两个基因对肿瘤的生长和转移都是必不可少的。2)浸润性炎症细胞，尤其是肿瘤相关巨噬细胞，可产生多种促癌细胞因子和生长因子。炎性趋化因子和细胞因子基因的遗传多态可能与乳腺癌的生存有关。3)转化生长因子-B促进乳腺癌的生长和发展，转化生长因子-受体通路基因的基因多态性可能与乳腺癌的生存有关。4)环氧合酶-2(COX2)基因在很大比例的乳腺肿瘤中上调，该酶启动多种前列腺素的生物合成，在肿瘤发生中有不同的，有时是相反的作用。前列腺素途径基因的遗传多态可能与乳腺癌的存活率有关。将采用两阶段研究设计。在第一阶段，所有功能变异加上单倍型标记SNPs将在1193名乳腺癌患者中进行基因分型，这些患者平均随访时间为7.1年。在第一阶段确定的所有有希望的关联将在第二阶段进行评估，这是一项对2400名癌症患者进行的队列研究(追踪5年)。大样本量和两阶段研究设计将平衡I型和II型错误，并为改善对遗传因素和乳腺癌预后之间的关系的理解提供可信的结果。确定预测复发风险和死亡率的因素，不仅将通过提供循证信息来影响不断扩大的癌症幸存者人口，而且还将通过使治疗更有效和更具成本效益，对医疗保健系统和整个经济产生积极影响。拟议的研究建立在成功实施的队列研究的基础上，将是非常及时和具有成本效益的。

DESCRIPTION (provided by applicant): The population of women who survive breast cancer is rising rapidly. Despite the success of initial treatments, many patients constantly battle fears of disease recurrence and early death. However, the effect of non-clinical factors, particularly genetic factors, on breast cancer outcomes is largely unknown. The proposed study will use the existing resources of two well-established cohort studies of 3593 breast cancer patients to comprehensively evaluate the following hypotheses: 1) Breast cancer survival may be associated with genetic polymorphisms in genes encoding angiogenic factors and matrix metalloproteinases, both of which are essential for tumor growth and metastasis. 2) Infiltrating inflammatory cells, particularly tumor- associated macrophages, can produce a large variety of promalignant cytokines and growth factors. Genetic polymorphisms in inflammatory chemokine and cytokine genes may be related to breast cancer survival. 3) Transforming growth factor-B promotes the growth and progression of breast cancer, and genetic polymorphisms in TGF-R pathway genes may be related to breast cancer survival. 4) The cyclooxygenase-2 (COX2) gene is up-regulated in a large proportion of mammary tumors, and this enzyme initiates the biosynthesis of various prostaglandins with diverse, and sometimes opposing, effects on tumorigenesis. Genetic polymorphisms of prostaglandin-pathway genes may be associated with breast cancer survival. A two-phase study design will be applied. In Phase I, all functional variants plus haplotype-tagging SNPs will be genotyped among 1193 breast cancer patients who have been followed for an average of 7.1 years. All promising associations identified in Phase I will be evaluated in Phase II in an on-going cohort study of 2400 cancer patients (being followed for 5 years). The large sample size and two-phase study design will balance both Type I and Type II errors and provide credible results towards improving the understanding of associations between genetic factors and breast cancer outcomes. Identifying factors that predict risk of relapse and rates of mortality will not only affect the expanding cancer survivor population by providing evidence-based information, but will also positively influence the medical care system and economy at large by making treatment more effective and cost-efficient. The proposed study, built on successfully implemented cohort studies, will be extremely timely and cost-efficient.