EARLY CANCER DETECTION AND SUSCEPTIBILITY BIOMARKERS

该提案是响应RFA CA-98-028早期检测研究网络/生物标志物发展实验室（EDRN/BDL），是匹兹堡大学癌症研究所（UPCI）的一个综合多学科项目，汇集了具有关键疾病部位相关专业知识的教师，包括膀胱癌、结直肠癌、肺癌/空气消化道和卵巢癌。对于每个站点，在基础癌症研究人员、生物统计学家、临床医生、外科医生和病理学家之间的持续互动下，一个主要的共同研究者和研究小组提出了创新的方法来发现新的早期癌症检测/易感性生物标志物，并对最近描述的生物标志物进行改进和初步验证。此外，两个在癌症基因突变和代谢酶/DNA修复基因多态性表征方面具有分子遗传学专长的研究小组将在几个器官部位的合作研究中应用这些端点。这些研究利用了广泛的UPCI临床基础设施和病理资源，这些资源是收集、组织病理学表征和处理组织/生物液体样本所必需的，部分原因是UPCI参与了最初的EDR网络。该项目研究的特异性生物标志物包括尿液中用于膀胱癌早期检测的独特的BLCA-4蛋白免疫测定；5q的LOH、APC K-ras和15外显子突变、iNOS和COX-2的表达作为结直肠癌的早期检测指标；卵巢肿瘤的SAGE分析发现外周血免疫测定标志物肺/气道活检样本中的ras和p53基因突变以及颊黏膜和外周血中EGF和GRP受体的表达作为HNSCC和NSCLC的早期检测生物标志物；以及CYP1A1、GSTM1、GSTT1、MPO和NAT2基因分型分析的应用，以及最近描述的DNA核苷酸切除修复（NER）基因XPD和XPF多态性的新分析的开发和验证，这些基因可作为膀胱癌、结直肠癌和/或肺癌/气消化癌的风险易感性标志物。这些研究活动将在积极整合的UPCI EDRN/BDL项目的背景下进行，由首席研究员推动，他在生物标志物的研究和分子流行病学应用方面具有丰富的经验和UPCI项目领导能力，在一个专注于癌症生物标志物发现、评估和验证的协作过程的环境中进行，以支持EDRN更广泛的研究和临床目标。

This proposal, in response to the RFA CA-98-028 Early Detection Research Network/Biomarkers Developmental Laboratories (EDRN/BDL), is an integrated multi-disciplinary project of the University of Pittsburgh Cancer Institute (UPCI) bringing together faculty with relevant expertise in key disease sites including bladder, colorectal, lung/aerodigestive tract, and ovarian cancer. For each site, a lead Co-Investigator and research group, with ongoing interactions among basic cancer researchers, biostatisticians, clinicians, surgeons, and pathologists, have proposed innovative approaches to the discovery of new early cancer detection/susceptibility biomarkers and refinement and initial validation of panels of recently described biomarkers. In addition, two research groups with molecular genetics expertise in the characterization of cancer gene mutations and metabolic enzyme/DNA repair gene polymorphisms will apply these endpoints in collaborative studies in several organ sites. These studies utilize the extensive UPCI clinical infrastructure and pathology resources necessary for the collection, histopathological characterization, and processing of tissue/biological fluid samples built, in part, upon UPCI's participation in the initial EDR Network. Specific biomarkers to be investigated in this project include a unique BLCA-4 protein immunoassay in urine for early detection of bladder cancer; LOH for 5q, mutation in K-ras and exon 15 of APC, and expression of iNOS and COX-2 as early detection markers of colorectal carcinoma; SAGE analysis of ovarian tumors for discovery of peripheral blood-based immunoassay markers; ras and p53 gene mutations in lung/airway biopsy samples and EGF and GRP receptor expression in buccal mucosa and peripheral blood as early detection biomarkers of HNSCC and NSCLC; and application of genotyping assays for CYP1A1, GSTM1, GSTT1, MPO, and NAT2 together with the development and validation of new assays for the recently-described polymorphisms in the DNA nucleotide excision repair (NER) genes XPD and XPF as risk susceptibility markers for bladder, colorectal, and/or lung/aerodigestive cancer. These research activities will be conducted in the context of an active integrated UPCI EDRN/BDL program, facilitated by the Principal Investigator who brings extensive experience and UPCI programmatic leadership in research and molecular epidemiological application of biomarkers, in an environment focused on a collaborative process of cancer biomarkers discovery, evaluation, and validation to support the broader research and clinical goals of the EDRN.