Bladder Cancer Prognostic Indicators

描述（由申请人提供）：美国每年有51，200人被诊断患有膀胱癌，10，600人死于该疾病。除了肿瘤的侵袭性、转移状态和细胞核分级外，肿瘤抑制基因的体细胞改变也被认为是膀胱癌治疗中有用的预后指标。然而，研究主要限于临床系列，这可能过度代表晚期病变。此外，DNA修复基因的多态性可能会影响膀胱癌的易感性和预后，损害正常修复的DNA损伤形成的暴露于DNA损伤剂。本研究项目的总体目标是调查影响膀胱癌发病率和预后的肿瘤标志物、遗传因素和环境暴露，使用通过新罕布什尔州的一项大型、基于人群的膀胱癌研究收集的数据和样本。具体而言，该研究将（1）检查DNA修复单倍型是否改变膀胱癌发病率，（2）通过肿瘤分期/分级评估总体膀胱癌复发率或存活率，以及（3）评估a）DNA修复途径中的体质遗传变异，B）环境暴露（如吸烟和砷）和c）体细胞标志物的预后意义：p53表达和染色体9 q杂合性丢失（洛）。在流行病学家Margaret Karagas博士（母病例对照研究的主要研究者）和分子生物学家约书亚汉密尔顿博士的指导下，这一指导性分子流行病学研究经验是达特茅斯医学院整合正式课程的培训计划的一部分。研究职业奖将使Angeline Andrew博士有机会发展她在癌症临床和分子流行病学方面的职业生涯，并将她的分子生物学背景与新的临床流行病学技能相结合，使她能够建立独立的转化研究计划。在对她的研究导师进行既定调查的基础上，安德鲁博士对预后指标的研究将能够更准确地评估肿瘤的侵袭性，指导适当的治疗方案，并最终帮助降低美国膀胱癌的死亡率。

DESCRIPTION (provided by applicant): Each year, 51,200 people in the US are diagnosed with bladder cancer and 10,600 die of the disease. In addition to tumor invasiveness, metastatic state and nuclear grade, somatic alterations in tumor suppressor genes have been proposed as useful prognostic indicators in the treatment of bladder cancers. Studies are largely limited to clinical series, however, which may over-represent advanced lesions. Furthermore, polymorphisms in DNA repair genes may affect bladder cancer susceptibility and prognosis by compromising the normal repair of DNA lesions formed by exposure to DNA damaging agents. The overall goal of this research project is to investigate tumor markers, genetic factors, and environmental exposures that affect bladder cancer incidence and prognosis using data and samples collected through a large, population-based study of bladder cancer in New Hampshire. Specifically, the study will (1) examine whether DNA repair haplotype modifies bladder cancer incidence, (2) assess overall bladder cancer recurrence or survival rates by tumor stage / grade, and (3) evaluate the prognostic significance of a) constitutional genetic variation in the DNA repair pathway, b) environmental exposures such as smoking and arsenic, and c) the somatic markers: p53 expression and loss of heterozygosity (LOH) of chromosome 9q. This mentored molecular epidemiology research experience under the guidance of the epidemiologist, Dr. Margaret Karagas, (Principal Investigator of the parent case - control study) and molecular biologist, Dr. Joshua Hamilton is part of a training proposal that integrates formal coursework at Dartmouth Medical School. The Research Career Award will give Dr. Angeline Andrew the opportunity to develop her career in the clinical and molecular epidemiology of cancer, and integrate her background in molecular biology with new clinical epidemiology skills, enabling her to establish an independent translational research program. Building on an established investigation of her research mentors, Dr. Andrew's study of prognostic indicators will enable more accurate assessment of a tumor's aggressiveness, guide appropriate treatment options, and ultimately aid the reduction of bladder cancer mortality in the US.