Genetic and Pharmacogenetic Modifiers of Cancer Risk and

DCEG在研究患者控制初始癌症的治疗与随后发展为第二种癌症的风险之间的关系方面有着悠久而杰出的历史。这代表了一种独特的观察情况，在这种情况下，人们可以研究人类暴露于明确定义的化学致癌物和电离辐射的后果。我们现在正在将这些研究转移到遗传领域，通过研究影响化学致癌物生物利用度的基因常见多态性以及DNA修复与各种临床结果之间的关系。这些研究可以确定具有第二种癌症、血栓形成事件、急性骨髓抑制、治疗反应甚至生存风险的人群亚群。识别基因变异也有可能降低不良后果的风险。此类信息可能对临床决策产生重大影响。(a) CGB的第一个药物遗传学项目的目标是与他莫昔芬和雌激素生物利用度有关的基因的遗传多态性，以及由于接触他莫昔芬而发生浸润性乳腺癌的风险。临床试验表明，接触他莫昔芬的女性患子宫内膜癌、深静脉血栓、肺泡栓塞和中风的风险增加，患乳腺癌的风险降低。一般来说，这些差异归因于他莫昔芬作为雌激素激动剂还是雌激素拮抗剂的组织特异性差异。我们假设，影响他莫昔芬和/或雌激素代谢的基因的遗传变异（单核苷酸多态性；“snp”）可能会确定哪些妇女亚群或多或少可能从他莫昔芬的施用中获益。该项目的第一阶段是针对参加NSABP的他莫昔芬乳腺癌预防试验（“P1”）的妇女，浸润性乳腺癌是研究的第一个结果。我们选择了“仅限病例”的研究设计。选择研究的40个多态性已完成基因分型，数据分析已进入最后阶段。手稿将于2007年初完成。该项目的后续阶段可能包括：(a)分析P1受试者中发生的非侵袭性乳腺癌；(b)同一研究中子宫内膜肿瘤的分析；(c)对整个P1队列的随机样本进行基因分型，以便寻找候选基因主要影响的证据，并获得所需的绝对风险估计（如果发现基因-他莫昔芬相互作用的证据），以便将这些发现应用于临床。(b)本项目领域的第二项主要研究是分析IGF1信号通路中基因的遗传多态性，以及作为晚期结直肠腺瘤危险因素的IGF1、IGF2和IGF-BP3的血清水平。IGF1是一种具有有丝分裂和抗凋亡作用的细胞因子，其水平升高与多种不同癌症的风险增加有关，包括绝经前乳腺癌、结肠癌、前列腺癌和肺癌。在与核心基因分型设施和流行病学与生物统计学项目主任办公室的合作下，这些基因的遗传变异和这三种肽的循环血清水平正在被系统地识别，然后在前列腺、肺癌、结肠癌和卵巢癌（PLCO）筛查试验的参与者中作为肿瘤风险的决定因素进行研究。第一阶段的目标是800名在基线结肠镜检查时发现患有晚期腺瘤性息肉的PLCO参与者，以及800名无息肉的对照组。目前正在研究8个IGF1信号通路基因中的60个单核苷酸多态性（snp）作为腺瘤风险的修饰因子。

DCEG has a long and distinguished history of investigating the relationship between treatments administered to patients to control an initial cancer, and the risk of subsequently developing a second cancer. This represents a unique observational situation in which one can study the consequences of human exposure to well-defined chemical carcinogens and to ionizing radiation. We are now moving these studies into the genetic arena, by investigating the relationship between common polymorphisms in genes affecting the bioavailability of chemical carcinogens as well as DNA repair, and various outcomes of clinical interest. Such studies could identify population sub-groups which are at particular risk of second cancers, thrombotic events, acute myelosuppression, response to treatment or even survival. The potential also exists to identify genetic variants which may reduce the risk of adverse outcomes. Information of this kind could have a significant impact on clinical decision-making. (a) CGB's first pharmacogenetics project targets genetic polymorphisms in the genes related to tamoxifen and estrogen bioavailability and the risk of developing invasive breast cancer as a result of exposure to tamoxifen. Clinical trials have demonstrated that women exposed to tamoxifen are at increased risk of endometrial cancer, DVT, PE as well as stroke, and at decreased risk of developing breast cancer. In general terms, these differences have been attributed to tissue specific variations in whether tamoxifen acts as an estrogen agonist or an estrogen antagonist. We hypothesize that genetic variants (single nucleotide polymorphisms; "SNPs") in the genes which affect tamoxifen and/or estrogen metabolism may identify sub-groups of women who are more or less likely to benefit from the administration of tamoxifen. The first phase of this project is targeting the women who participated in NSABP's Tamoxifen Breast Cancer Prevention Trial ("P1"), with invasive breast cancer the first outcome to be investigated. A "case-only" study design has been chosen. Genotyping has been completed for the 40 polymorphisms selected for study is complete, and data analysis has entered its final stages. A manuscript should be complete early in 2007. Subsequent phases of this project may include: (a) analysis of the non-invasive breast cancers which developed in P1 subjects; (b) analysis of the endometrial neoplasms from this same study; and (c) genotyping of a random sample of the entire P1 cohort, to permit seeking evidence of a major effect for candidate genes, and to obtain the absolute risk estimates required (if evidence of a gene-tamoxifen interaction is found) to apply these findings clinically.(b) The second major study within this program area is an analysis of genetic polymorphisms in genes which are part of the IGF1 signaling pathway, and serum levels of IGF1, IGF2 and IGF-BP3, as risk factors for advanced colorectal adenoma. Elevated levels of IGF1, a cytokine with both mitogenic and anti-apoptotic effects, have been associated with increased risks of a variety of different cancers, including premenopausal breast, colon, prostate and lung cancer. In collaboration with the Core Genotyping Facility and the Office of the Director, Epidemiology & Biostatistics Program, genetic variations in these genes and circulating serum levels of these three peptives are being systematically identified and then studied as determinants of neoplasm risk among participants of the Prostate, Lung, Colon and Ovarian Cancer (PLCO)screening trial. The first phase has targeted 800 PLCO participants who were found to have advanced adenomatous polyps at the time of their baseline colonscopy, and 800 polyp-free controls. Sixty (60) single nucleotide polymorphisms (SNPs) in eight of the IGF1 signaling pathway genes are being studied as modifiers of adenoma risk.