AB011. Systematic analysis of the genomic landscapes of genitourinary cancers

Objective: Genitourinary cancers, including all types of cancers originated from the genitourinary system, affect 15% of patients with cancer. Molecular targets for the diagnosis and treatment of these diseases are scant and ineffective as the genetic backgrounds of genitourinary cancers have not been fully elucidated. Here, we explored the genetic landscapes for two of the most common types of genitourinary cancers (bladder and kidney cancer) to provide evidences for personalized care for the patients with genitourinary cancers.

Methods: We analyzed the exomes of nine individuals with bladder transitional cell carcinoma (TCC) and ten clear cell renal cell carcinomas (ccRCC) by deep sequencing, and screened the somatically mutated genes in additional large cohorts of patients. We also carried out single-cell exome sequencing on a ccRCC tumor and its adjacent kidney tissue to assess the extent of intratumor heterogeneity.

Results: We identified frequent genetic aberrations of the chromatin remodeling genes, and genes involved in sister chromatid cohesion and segregation (SCCS) in subjects with bladder TCC. Of these genes, UTX (in 21% of subjects) is substantially altered more frequently in tumors of low stages and grades. We also showed that 21% of ccRCC patients harboring mutations in the ubiquitin-mediated proteolysis pathway (UMPP), and alterations in the UMPP were significantly associated with overexpression of HIF1α and HIF2α in the tumors. Furthermore, by using single-cell exome sequencing on a ccRCC tumor, we found that the tumor did not contain any significant funding clones and mutations that had different allele frequencies within the tumor cell populations also had different mutation spectrums.

Conclusions: Our results provide an overview of the genetic basis of bladder TCC and suggest that aberration of chromatin regulation and the SCCS process might be a hallmark of bladder cancer. Our findings also highlight the potential contribution of UMPP to ccRCC tumorigenesis through the activation of the hypoxia regulatory network and demonstrate ccRCC to be more genetically complex than previously thought. Our systematic analysis of the genitourinary cancers provides information that can lead to new ways to investigate individual tumors, with the aim of developing more effective cellular targeted therapies.

Keywords: Genitourinary cancers; bladder cancer; renal cancer; deeping sequencing