Genomic characterization of high-risk non-muscle invasive bladder cancer

Joshua J. Meeks*, Benedito A. Carneiro, Sachin G. Pai, Daniel T. Oberlin, Alfred Rademaker, Kyle Fedorchak, Sohail Balasubramanian, Julia Elvin, Nike Tsiapera Beaubier, Francis J. Giles

*Corresponding author for this work

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The genetic mechanisms associated with progression of high-risk non-muscleinvasive bladder cancer (HR-NMIBC) have not been described. We conducted selective next-generation sequencing (NGS) of HR-NMIBC and compared the genomic profiles of cancers that responded to intravesical therapy and those that progressed to muscleinvasive or advanced disease. DNA was extracted from paraffin-embedded sections from 25 HR-NMIBCs (22 with T1HG; 3 with TaHG with or without carcinoma in situ). Ten patients with HR-NMIBC developed progression (pT2+ or N+) ("progressors"). Fifteen patients had no progression ("non-progressors"). Tissue from 11 patients with metastatic bladder cancer (BC) were analyzed for comparison. We found no difference in frequency of mutations of TP53, PIK3CA, or KMT2D between the primary tumors of progressors compared to non-progressors and metastatic tumors. An increased frequency of deletions of CDKN2A/B was identified in tumors at progression (37%) compared to non-progressors (6%) (p = 0.10). We found a significant decrease in total mutational burden (TMB) that has been associated with immunotherapy response comparing nonprogressors, progressors and metastatic tumors at 15, 10.1 and 5.1 mutations/MB respectively (p = 0.02). This association suggests more advanced tumors have decreased neoantigen burden and may explain the mechanism of BCG response in non-progressors. We found no novel genetic drivers in progressors and HR-NMIBC had many genetic features similar to metastatic BC. Loss of CDKN2A/B may occur late during invasion of BC and may represent an important step in progression. Further research is necessary to evaluate TMB and loss of CDKN2A/B locus as a biomarker for progression of NMIBC.

Original languageEnglish (US)
Pages (from-to)75176-75184
Number of pages9
JournalOncotarget
Volume7
Issue number46
DOIs
StatePublished - Jan 1 2016

Keywords

  • Bladder cancer
  • Invasion
  • Mutation burden
  • Progression

ASJC Scopus subject areas

  • Oncology

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    Meeks, J. J., Carneiro, B. A., Pai, S. G., Oberlin, D. T., Rademaker, A., Fedorchak, K., Balasubramanian, S., Elvin, J., Beaubier, N. T., & Giles, F. J. (2016). Genomic characterization of high-risk non-muscle invasive bladder cancer. Oncotarget, 7(46), 75176-75184. https://doi.org/10.18632/oncotarget.12661