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。除了肿瘤侵袭性、转移状态和核分级外，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，研究主要局限于临床系列，这可能过度代表晚期病变。此外，DNA修复基因的多态性可能通过影响暴露于DNA损伤剂形成的DNA损伤的正常修复而影响膀胱癌的易感性和预后。本研究项目的总体目标是研究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，使用的数据和样本是通过在新罕布什尔州进行的一项大规模、基于人群的膀胱癌研究收集的。具体而言，该研究将（1)检查DNA修复单倍型是否改变膀胱癌的发病率，（2)根据肿瘤分期/分级评估膀胱癌的总体复发率或生存率，以及(3)评估a） DNA修复途径中的体质遗传变异，b）吸烟和砷等环境暴露，以及c)体细胞标记：p53表达和染色体9q杂合性缺失（LOH）的预后意义。在流行病学家Margaret Karagas博士（父母病例对照研究的首席研究员）和分子生物学家Joshua Hamilton博士的指导下，这种受指导的分子流行病学研究经验是整合达特茅斯医学院正式课程的培训计划的一部分。研究事业奖将给予Angeline Andrew博士在癌症临床和分子流行病学方面发展事业的机会，并将她在分子生物学方面的背景与新的临床流行病学技能相结合，使她能够建立一个独立的转化研究项目。基于对其研究导师的既定调查，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，指导适当的治疗选择，并最终有助于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.