Project description:This study funded by the National Cancer Institute (NCI) involves conducting a genome-wide association study of common genetic variants to identify markers of susceptibility to bladder cancer. This bladder GWAS has led to the discovery of three novel regions in the genome associated with bladder cancer risk. Cases were defined as individuals having histologically confirmed primary carcinoma of the urinary bladder, including carcinoma in situ (ICD-0-2 topography codes C67.0-C67.9 or ICD9 codes 188.1-188.9). Scan data were obtained from two case-control studies carried out in Spain and the United States (specifically, those in the Maine and Vermont components of the New England Bladder Cancer Study) and three prospective cohort studies in Finland and the United States (specifically Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, and The American Cancer Society Cancer Prevention Study II Nutrition Cohort). We used data from 591,637 single nucleotide polymorphisms 3,532 affected individuals (cases) and 5,119 controls of European descent and replication including 8382 cases and 48275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P ≈ 8 x 10-12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 x 10-11) on maps to CCNE1 and rs11892031 (P = 1 x 10-7) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3 (Rothman N et al., Nature Genetics, 2010, PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/20972438" target="_blank">20972438</a>). Through meta-analysis with the MD Anderson Texas Bladder Cancer Study (TXBCS), we also identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 (P = 8.7 x 10(-9); allelic odds ratio 1.20 with 95% CI: 1.13-1.28) and two highly correlated SNPs, rs10775480/rs10853535 (r(2)= 1.00; P = 8.9 x 10(-9); allelic odds ratio 1.16 with 95% CI: 1.10-1.22) (Garcia-Closas M et al, Human Molecular Genetics, 2011) For NCI-GWAS2, we performed genotyping on cases and controls for the New Hampshire component of the New England Bladder Cancer Study (NEBCS-NH). For the majority of new bladder cancer cases, we genotyped only cases from four case-control studies, the Los Angeles Bladder Cancer Study (LABCS), the French Center for Research on Prostate Diseases (CeRePP), the French Bladder Study (FBCS) and the Brescia Bladder Cancer Study (BBCS). We used existing control data from four cohort studies already genotyped and subjected to rigorous quality control metrics: the European Prospective Investigation Into Cancer and Nutrition Study (EPIC), Womens Health Initiative (WHI), Health Professionals Follow-up Study (HPFS), Nurses Health Study (NHS), which have been a part of Cancer Genetic Markers of Susceptibility (CGEMS). Meta-analysis of NCI-GWAS1, NCI-GWAS2 and a previously reported GWAS TXBCS-GWAS along with taqman replication, identified two new loci: rs10936599 on 3q26.2 (P = 4.53 x 10(-9)) and rs907611 on 11p15.5 (P = 4.11 x 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 x 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 X 10(-7)); these require further studies for confirmation (Figueroa J et al, Human Molecular Genetics, 2013).

Project description:This study aimed to identify the genetic signatures associated with disease prognosis in bladder cancer. We used 165 primary bladder cancer samples, 23 recurrent non-muscle invasive tumor tissues, 58 normal looking bladder mucosae surrounding cancer and 10 normal bladder mucosae for microarray analysis. Hierarchical clustering was used to stratify the prognosis-related gene classifiers. For validation, real-time reverse-transcriptase polymerase chain reaction (RT-PCR) of top-ranked 14 genes was performed. On unsupervised hierarchical clustering using prognosis related gene-classifier, tumors were divided into 2 groups. The high risk gene signatures had significantly poor prognosis compared to low risk gene signatures (P<0.001 by the log-rank test, respectively). The prognosis-related gene classifiers correlated significantly with recurrence of non-muscle invasive bladder cancer (hazard ratio, 4.09; 95% confidence interval [CI], 1.94 to 8.64; P<0.001), and progression (hazard ratio, 23.68; 95% confidence interval [CI], 4.91 to 114.30; P<0.001), cancer-specific survival (hazard ratio, 29.25; 95% confidence interval [CI], 3.47 to 246.98; P=0.002) and overall survival (hazard ratio, 23.33; 95% confidence interval [CI], 4.97 to 109.50; P<0.001) of muscle invasive bladder cancer (p < 0.001, respectively). No patient with non-muscle invasive bladder cancer experienced cancer progression in low risk gene signature group. Prognosis-related gene classifiers validated by RT- PCR showed identical results. Prognosis related gene-classifiers provided strong predictive value for disease outcome. These gene classifiers could assist in selecting patients who might benefit from more aggressive therapeutic intervention or surveillance. Keywords: Gene expression, Bladder cancer, Prognosis 165 primary bladder cancer samples and 23 recurrent non-muscle invasive tumor tissues from 14 patients were taken in the Chungbuk National University Hospital. Only histologically verified transitional cell carcinoma samples were selected. Simultaneously 58 normal looking bladder mucosae surrounding cancer were obtained during the operation, which were histologically confirmed normal. Also, 10 normal bladder mucosae were obtained from patients with benign disease. The normal controls were determined to be free of cancer after revealing no malignant cells on urine cytology and no observable bladder cancer on cystoscopic examination during operation for their diseases, and were histologically reconfirmed normal.

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New England Bladder Cancer Study (NEBCS)

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