Comprehensive Molecular Characterization of Urachal Adenocarcinoma Reveals Commonalities With Colorectal Cancer, Including a Hypermutable Phenotype

Authors

Jordan Kardos

Jordan Kardos, Sara E. Wobker, Michael E. Woods, Matthew E. Nielsen, Angela B. Smith, Eric M. Wallen, Raj S. Pruthi, Michele C. Hayward, Katrina A. McGinty, Juneko E. Grilley-Olson, Nirali M. Patel, Karen E. Weck, Joel S. Parker, Matthew I. Milowsky, D. Neil Hayes, and William Y. Kim, University of North Carolina at Chapel Hill, Chapel Hill, NC; and Peter Black, University of British Columbia, Vancouver, British Columbia, Canada.

Jordan Kardos, Sara E. Wobker, Michael E. Woods, Matthew E. Nielsen, Angela B. Smith, Eric M. Wallen, Raj S. Pruthi, Michele C. Hayward, Katrina A. McGinty, Juneko E. Grilley-Olson, Nirali M. Patel, Karen E. Weck, Peter Black, Joel S. Parker, Matthew I. Milowsky, D. Neil Hayes, William Y. Kim

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Purpose

Urachal adenocarcinoma is a rare type of primary bladder adenocarcinoma that comprises less than 1% of all bladder cancers. The low incidence of urachal adenocarcinomas does not allow for an evidence-based approach to therapy. Transcriptome profiling of urachal adenocarcinomas has not been previously reported. We hypothesized that an in-depth molecular understanding of urachal adenocarcinoma would uncover rational therapeutic strategies.

We performed targeted exon sequencing and global transcriptome profiling of 12 urachal tumors to generate a comprehensive molecular portrait of urachal adenocarcinoma. A single patient with an MSH6 mutation was treated with the anti–programmed death-ligand 1 antibody, atezolizumab.

Urachal adenocarcinoma closely resembles colorectal cancer at the level of RNA expression, which extends previous observations that urachal tumors harbor genomic alterations that are found in colorectal adenocarcinoma. A subset of tumors was found to have alterations in genes that are associated with microsatellite instability (MSH2 and MSH6) and hypermutation (POLE). A patient with an MSH6 mutation was treated with immune checkpoint blockade, which resulted in stable disease.

Because clinical trials are next to impossible for patients with rare tumors, precision oncology may be an important adjunct for treatment decisions. Our findings demonstrate that urachal adenocarcinomas molecularly resemble colorectal adenocarcinomas at the level of RNA expression, are the first report, to our knowledge, of MSH2 and MSH6 mutations in this disease, and support the consideration of immune checkpoint blockade as a rational therapeutic treatment of this exceedingly rare tumor.