Genetic analysis of two bladder exstrophy populations of South Asian and North American origin

Bladder exstrophy-epispadias complex (BEEC) is a devastating congenital anomaly of the urinary tract and is associated with an increased risk of bladder cancer. The etiology of the BEEC is unknown, but a clear genetic component has been highlighted. Currently, all genetic studies suffer from small populations, limited to a European background.

To identify copy number variations (CNVs) in a South Asian and North American bladder exstrophy cohorts. To identify novel non-European CNVs to expand the literature beyond its European ethnic background.

Patients from our South Asian and North American cohorts had DNA isolated from peripheral blood samples and biobanked at the Children Hospital of Philadelphia's (CHOP) Center for Applied Genomics (CAG). DNA Genotyping was performed with various arrays for the North American cohort and the Illumina Global Screening Array for the South Asian cohort. Controls for both cohorts were identified from CHOP's CAG and ethnicity matching by principle component analysis was performed. CNV calling and filtering were performed with PennCNV and ParseCNV, respectively.

The North American and South Asian cohorts included 53 and 97 patients, respectively. Fifty-five statistically significant CNVs were identified across three independent analyses, of which 53 (96.4 %) were novel to the BE literature. Thirteen of our CNVs were near (within 100 million base pairs) but not in linkage disequilibrium with 8 previously identified BEEC genome-wide association study (GWAS) loci. One of our CNVs (chr16: 28,635,133-28,636,902) was near a previously reported CNV of clinical significance (chr16:29,645,396-30,168,276). Seventeen CNVs contained 15 distinct genes associated with cancer, of which 10/15 (66.7 %) have reported associations in bladder cancer.

We present the first genetic analysis of a non-European cohort of bladder exstrophy patients. Our study identified a high number of novel CNVs containing cancer predisposition genes mostly distinct from those found in European cohorts. Limitations inherent to BEEC research include small sample sizes which required intermixing of all phenotypes of the BEEC spectrum (epispadias to cloacal exstrophy). These data highlight the importance of multi-institutional and international collaboration to create ethnically diverse cohorts and allow for severity-specific genetic analyses of the different phenotypes within the BEEC.

We identified novel CNVs with distinct cancer predisposition genes in the first study to expand the BEEC literature beyond its European ethnic background. Additional studies in other non-European cohorts are needed to expand our understanding of the genetic landscape of BEEC.