CLINICAL AND EPIDEMIOLOGIC CENTER FOR BIOMARKERS

我们建议创建一个专注于上呼吸道(UADT)损伤生物标记物的临床和流行病学中心，这是研究风险标记物、早期发现和干预反应的极好模型。我们将建立在资助的组间化学预防试验和流行病学研究的基础上，这些试验和流行病学研究涵盖了UADT疾病的整个过程，从癌前病变到第二原发肿瘤的风险。我们建议：1.临床资源：我们有批准的方案、跟踪系统、积极的随访和关于参加化学预防和流行病学UADT研究的受试者的大量初步数据。我们可以通过我们多样化的患者群体、流行病学研究的比较对象以及我们自己中心的癌症遗传学网络的基础设施来扩大资源。2.生物标记物资源：整合了在胚系DNA、癌前病变、邻近正常上皮和浸润性癌中表达的风险、早期检测和干预反应的综合生物标记物。这些包括组织标记--例如，基因组不稳定标记(染色体多倍体，9p21、3p14和17p的杂合性缺失)、增殖、p53、细胞周期蛋白D1、EGFR和RAR表达--以及风险标记--例如表型(体外淋巴细胞分析)和遗传型(代谢多态)。3.相互关联的研究项目(3)评估有希望的候选遗传和表型细胞和分子生物标记物，可用于描述该领域和多步骤UADT肿瘤发生过程，并用于评估早期和晚期毛孔恶性病变以及UADT的第一和多发癌的风险、早期发现和反应。4.结合生物标记物数据的统计方法；评估基因型/表型和代理/目标组织标记物的相关性；以及开发第二原发肿瘤的风险评估模型。5.烟草引起的上皮性癌症，如膀胱癌的生物标记物的开发项目。6.与业界合作，验证微阵列技术，对一系列多态代谢易感基因进行大规模基因分型。7.与悬而未决的针对膀胱癌的Biomarker开发赠款合作(B.Czerniak，P.I.)总体而言，我们在烟草致癌易感性、化学预防干预措施和生物标志物分析方面的基础、临床、转化和流行病学研究方面拥有长期和成功的记录。因此，我们有了拟议研究的相关课题；我们有令人信服的初步数据；我们有必要的专门知识和组织结构，可以最大限度地取得成功。调查小组是多学科的，将能够以及时和灵活的方式对网络指令作出反应，并加强和增强网络的研究能力。

We propose to create a Clinical and Epidemiologic Center focused on Biomarkers for Upper Aerodigestive Tract (UADT) Lesions, an Excellent model for studying markers of risk, early detection and response to intervention. We will build upon funded intergroup chemopreventive trials and epidemiologic studies that span the continuum of UADT disease, from pre-malignant lesions to risk of second primary tumors. We propose: 1. A Clinical Resource: We have approved protocols, tracking systems, active follow-up and substantial preliminary data on subjects enrolled in chemoprevention and epidemiologic UADT studies. We can expand the resource with our diverse patient population, comparison subjects from epidemiologic studies, and the infrastructure from our own center's Cancer Genetics Network. 2. Biomarker Resource: Integration of a comprehensive panel of biomarkers of risk, early detection and response to intervention expressed in germline DNA, premalignant lesions, adjacent normal epithelium, and invasive cancers. These include tissue markers-e.g., genomic instability markers (chromosomal polysomy, LOH of 9p21, 3p14, and 17p), proliferation, p53, cyclin D1, EGFR, and RAR expression- and risk markers-e.g., phenotypic (in vitro lymphocyte assays) and genotypic (metabolic polymorphisms). 3. Inter-related research projects (3) to evaluate promising candidate genetic and phenotypic cellular and molecular biomarkers useful for characterizing the field and the multi-step UADT tumorigenesis process; and for assessment of risk, early detection, and response in early and advanced pore-malignant lesions and first and multiple cancers of the UADT. 4. Statistical methodologies for combining biomarker data; for assessing genotype/phenotype and surrogate/target tissue marker correlations; and to develop a risk assessment model for second primary tumors. 5. Developmental projects in biomarkers for tobacco-induced epithelial cancers e.g. bladder cancer. 6. Collaboration with industry to validate microarray technology to perform large scale genotyping of a range of polymorphic metabolic susceptibility genes. 7. Collaboration with a pending Biomarker Development Grant on Bladder Cancer (B. Czerniak, P.I.) Collectively, we have a long and successful track record of basic, clinical, translational, and epidemiologic research in susceptibility to tobacco carcinogenesis, in chemopreventive interventions, and in biomarker analysis. Thus, we have the relevant subjects for our proposed studies; we have compelling preliminary data; and we have the necessary expertise and organization structure to maximize success. The team of investigators is multi-disciplinary and will be able to respond in a timely and flexible manner to network directives, and to enhance and augment the network's research capabilities.