Analysis of Somatic Mutations in Cancer of the Kidney

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Obesity, hypertension, and heavy cigarette smoking are suspected risk factors for kidney cancer, although the actual mechanisms by which these factors exert their action remain to be elucidated. Because the type of p53 gene mutation has provided clues as to etiology for several cancers (e.g., in bladder cancer and renal pelvic carcinoma it has been established that G:C->A:T transitions in p53 result from tobacco smoke carcinogens), and because we have access to DNA from 1,141 newly diagnosed renal cell carcinoma cases in the INCO Central Europe Health Study (CEHS), this NCI R03 project will evaluate whether there is a relationship between p53 gene mutation characteristics and certain selected risk factor characteristics in renal cell carcinoma. The results will help elucidate potential etiologic pathways for kidney cancer that will be pursued in subsequent studies. The CEHS is a hospital-based case-control study of environmental and genetic risk factors for kidney cancers at six centers across Central and Eastern Europe. Funded intramurally by NCI Division of Cancer Epidemiology and Genetics and IARC, the CEHS used an extensive in-person questionnaire to assess general lifestyle, medical and drug use history, family history, use of tobacco products, exposure to environmental tobacco smoke, residential history, alcohol and dietary information, and a detailed occupational history in the 1,141 cases and in 1,157 age-matched controls. Blood samples were collected on all 2,300 participants for genotyping of specific single nucleotide polymorphisms in genes encoding enzymes that are in well characterized metabolic pathways for a variety of environmental and occupational carcinogens, as well as for genes involved in DNA repair, immune function, and cell cycle control. Tumor tissue was collected and DNA was extracted at the NCI. Aim 1 is to determine the frequency, spectrum and specificity of p53 gene mutations from the DNA of each CEHS kidney cancer case. Exons 4-9 will be evaluated for mutations using denaturing high-performance liquid chromatography, which will be followed by sequencing to determine the exact nature of the mutation. Aim 2, in collaboration with Environmental Cancer Epidemiology Unit at IARC, is to use the p53 gene mutation data together with the lifestyle and occupational data on the cases to test specific etiologic hypotheses: (A) Is there a correlation between tobacco smoke exposure and p53 gene mutation spectrum? Do the kidney cancer patients with the highest levels of tobacco smoke exposure have a higher prevalence of p53 gene mutation and gene mutation spectrums that resemble the patterns associated with exposure to tobacco in bladder cancer and renal pelvic carcinoma patients? These analyses will be stratified by (i) never smokers versus ever smokers, (ii) duration and (iii) intensity of exposure. (B) Is there a correlation between other suspected risk factors, hypertension and obesity, and p53 gene mutation prevalence and spectrum? (C) Is there a correlation between survival and p53 gene mutation prevalence and spectrum?