Bladder Cancer Prognostic Indicators

描述(申请人提供)：在美国，每年有51,200人被诊断出患有膀胱癌，10,600人死于这种疾病。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变化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修复基因的多态可能通过影响因接触DNA损伤剂而形成的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利用在新罕布夏州进行的一项基于人群的大型膀胱癌研究收集的数据和样本，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。具体地说，这项研究将(1)检查DNA修复单倍型是否改变膀胱癌发病率，(2)根据肿瘤分期/分级评估总体膀胱癌复发或生存率，(3)评估a)DNA修复途径中的结构性遗传变异，b)环境暴露，如吸烟和砷，以及c)体细胞标记物：P53表达和9q染色体杂合性缺失(LOH)的预后意义。在流行病学家玛格丽特·卡拉加斯博士(父母病例对照研究的首席研究员)和分子生物学家约书亚·汉密尔顿博士的指导下，这项指导分子流行病学研究的经验是达特茅斯医学院正规课程整合培训计划的一部分。研究职业奖将使Angeline Andrew博士有机会在癌症的临床和分子流行病学方面发展她的事业，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翻译研究计划。在对她的研究导师的既定调查的基础上，安德鲁博士对预后指标的研究将使人们能够更准确地评估肿瘤的侵袭性，指导适当的治疗方案，并最终有助于降低美国的膀胱癌死亡率。

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.