Biology of Virus-associated Cancers

Division Of Basic Sciences - Nci

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Abstract

Solid organ transplant recipients are at an increased risk for developing bladder cancer compared to the general population. Kidney transplant recipients (KTR) with a previous history of BK polyomavirus (BKPyV) viremia have an even further increased risk, and the involvement of this virus in bladder carcinogenesis has been speculated for years. Only through recent advances in sample processing and next-generation sequencing has it become more evident that this virus plays a role in at least a small subset of cancers, but the exact nature and extent of this involvement is unclear. However, previous studies have been limited by number of patients or experimental approach. We have collected a cohort of 43 KTRs who have gone on to develop urinary bladder cancer. So far, we have successfully extracted RNA and DNA and performed total RNA and whole genome sequencing. The results from this project confirmed the increased involvement of BK polyomavirus in this subset of cancer and raised the possibility of greater viral involvement. To experimentally study the interplay between BKPyV and bladder cancer we have implemented several cellular models. First using bladder cancer cell lines, we have identified several line that are deficient for viral replication, which may provide insights into how tumors may lose viral gene expression in late stage tumors. We have also engineered bladder cells to remove the primary mutagenic enzymes responsible for the somatic mutations observed in bladder cancer and in BKPyV evolution. These lines will be used in organotypic culture to study both host and viral mutagenesis. Further we are also using chromatin conformation sequencing to study how polyomaviruses in general erroneously integrate into the host genome and cause cancer. Lastly, we are applying the same technologies used for bladder cancer to study sebaceous carcinoma, which is also at a dramatically increased incidence in immunosuppressed patients and loosely tied to infection with HPV16. We have completed RNA sequencing and WGS for nearly 70 sebaceous carcinomas and its precursor sebaceous adenoma and will be receiving 120 more tumor specimens and controls in the coming year.