M8 - NCI GWAS in bladder cancer

Investigator Names and Contact Information

Stephen Chanock (chanocks@mail.nih.gov)

Introduction/Intent

Bladder cancer is a major public health problem with high disease management costs because of high recurrence of tumors requiring frequent screening and interventions (of particular relevant for early stage tumors). There are well-known epidemiologic factors that are associated with increased risk for bladder cancer; these include smoking and occupational exposure to aromatic amines (3), plus important clues for environmental, medication use, and lifestyle risk factors, as well as fluid balance and urine pH. The portfolio of established risk factors should provide opportunities to evaluate risk factors stratified by genotype and genetic factors within distinct exposure subgroups. There is also good evidence for a genetic component, given that previous studies have demonstrated reproducible associations with NAT2 and GSTM1 genotypes (4). Further, gene-environment interactions have been shown for smoking and specific NAT2 genotypes (4). The modest familial association has not yet been explained but supports the value of searching of genetic determinants of bladder cancer. Together these observations develop a strong case for investigation of multigenic associations as well as gene-environment interactions. Adequate information on outcome and tumor recurrence is available, particularly in the study to be analyzed in the GWAS. Thus, there is an excellent opportunity to explore the influence of genetic variants on tumor recurrence and survival, which could have potentially important clinical implications. Results from a GWAS leading to the identification of genetic makers could provide a major advance in our understanding of the biological mechanisms underlying bladder cancer pathogenesis. The GWAS with replication studies could also identify additional modifiable factors that increase bladder cancer risk, recurrence and survival. The potential is great for advancing the understanding of the genetic contribution to bladder cancer, which could establish the foundation for developing novel approaches towards prevention while decreasing the burden of bladder cancer.

We are proposing to conduct a genome-wide association study (GWAS) of common genetic variants to identify genetic markers of susceptibility to bladder cancer. The initial scan will be conducted in 1,000 bladder cancer cases and 1,000 controls from the Spanish Bladder Cancer Study, a hospital-based case-control study, with a dense set of one million single nucleotide polymorphisms (SNPs) with minor allele frequencies (MAF) > 5% that can serve as markers for approximately 90% of all common SNPs in Caucasians. We will carry out a second primary scan of 610,000 SNPs on 1,000 cases and 1,000 controls from the New England Bladder Cancer Study, a population-based case-control study. We will then carry out a replication scan on bladder cancer cases from the PLCO Trial, the ATBC study, the American Caner Society CPSII cohort, and are proposing to include the Women’s Health Initiative study as well. The estimated total sample size for a replication phase including the four cohorts is about 2,000 cases and 2,000 controls. Replication studies are critical to the success of GWAS and should be considered integral to the determination of genetic susceptibility to bladder cancer (1;2). We anticipate that SNPs highly likely to be markers for genetic variants related to bladder cancer risk will emerge from this analysis and lead to further studies of gene-gene and gene-environment interactions with bladder cancer risk factors, particularly cigarette smoking. Analyses will also be performed among the cases with available follow up data to identify genetic markers that could predict patterns of tumor recurrence and survival. In order to accelerate the pace of discovery and characterization of genetic markers associated with bladder cancer risk, the results of the GWAS and the final pre-computed analysis of the GWAS and replication studies will be made available to the research community. The genotyping data from the GWAS will also be posted on a controlled-access web site, available to the biomedical research community.

Aims

1. The primary aim of the GWAS for bladder cancer will be to identify novel genetic variants with different frequencies in cancer cases and controls that are worthy of further pursuit in epidemiological, genetic mapping population, clinical and laboratory investigations.
2. Using the best candidates from the GWAS and validation studies, the GWAS for bladder cancer will establish a foundation for the investigation of gene-gene and gene-environment\behavioral interactions, particularly interactions with tobacco smoking. Inclusion of the cohort studies with prospective collection of questionnaire data and biological specimens will be very valuable for the evaluation of gene-environment interactions, and will also enable the evaluation of relationships with biomarkers of exposure and intermediate endpoints in future studies that may evolve from the GWAS effort.
3. The design of the GWAS study enables case only analysis to identify genetic markers that could be associated with tumor recurrence and/or survival for those studies that collect this information.
4. The pre-computed summary analyses of each SNP will be available on a publicly accessible data portal (identical to what is currently used for CGEMS) in order to accelerate the discovery and replication of genetic variants associated with the risk for bladder cancer. The de-linked genotype results with limited co-variates will be publicly accessible through a controlled-access registered website within months after completion and assessment of quality control analyses. Requesting investigators will require institutional verification for access to controlled data for research purposes only.

References

(1) Chanock SJ, Manolio T, Boehnke M, Boerwinkle E, Hunter DJ, Thomas G et al. Replicating genotype-phenotype associations. Nature 2007; 447(7145):655-660.

(2) Skol AD, Scott LJ, Abecasis GR, Boehnke M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet 2006; 38(2):209-213.

(3) Silverman DT, Devesa SS, Moore LE, Rothman N. Bladder cancer. In: Schottenfeld D, Fraumeni JF Jr, editors. Cancer Epidemiology and Prevention. New York, NY: Oxford University Press, 2006: 1101-1127.

(4) Garcia-Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M, Hein DW et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 2005; 366:649-659.