Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations

Cancer. 2016 Mar 1;122(5):702-11. doi: 10.1002/cncr.29826. Epub 2015 Dec 9.

Abstract

Background: In the current study, the authors present a comprehensive genomic profile (CGP)-based study of advanced urothelial carcinoma (UC) designed to detect clinically relevant genomic alterations (CRGAs).

Methods: DNA was extracted from 40 µm of formalin-fixed, paraffin-embedded sections from 295 consecutive cases of recurrent/metastatic UC. CGP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of 688X for all coding exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer, using process-matched normal control samples as a reference. CRGAs were defined as GAs linked to drugs on the market or currently under evaluation in mechanism-driven clinical trials.

Results: All 295 patients assessed were classified with high-grade (International Society of Urological Pathology classification) and advanced stage (stage III/IV American Joint Committee on Cancer) disease, and 294 of 295 patients (99.7%) had at least 1 GA on CGP with a mean of 6.4 GAs per UC (61% substitutions/insertions/deletions, 37% copy number alterations, and 2% fusions). Furthermore, 275 patients (93%) had at least 1 CRGA involving 75 individual genes with a mean of 2.6 CRGAs per UC. The most common CRGAs involved cyclin-dependent kinase inhibitor 2A (CDKN2A) (34%), fibroblast growth factor receptor 3 (FGFR3) (21%), phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (20%), and ERBB2 (17%). FGFR3 GAs were diverse types and included 10% fusions. ERBB2 GAs were equally divided between amplifications and substitutions. ERBB2 substitutions were predominantly within the extracellular domain and were highly enriched in patients with micropapillary UC (38% of 32 cases vs 5% of 263 nonmicropapillary UC cases; P<.0001).

Conclusions: Using a CGP assay capable of detecting all classes of GA simultaneously, an extraordinarily high frequency of CRGA was identified in a large series of patients with advanced UC. Cancer 2016;122:702-711. © 2015 American Cancer Society.

Keywords: bladder cancer; comprehensive genomic profiling; cyclin-dependent kinase inhibitor 2A (CDKN2A); fibroblast growth factor receptor (FGFR); metastatic; micropapillary.

MeSH terms

  • Aged
  • Carcinoma, Transitional Cell / genetics*
  • Carcinoma, Transitional Cell / pathology
  • Carcinoma, Transitional Cell / secondary
  • Class I Phosphatidylinositol 3-Kinases
  • Databases, Factual
  • Female
  • Gene Amplification
  • Gene Deletion
  • Gene Fusion
  • Gene Rearrangement
  • Genes, erbB-2
  • Genes, p16
  • Genes, p53
  • Genetic Variation / genetics*
  • Humans
  • Male
  • Mutation
  • Neoplasm Metastasis / genetics
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / pathology
  • Phosphatidylinositol 3-Kinases / genetics
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology

Substances

  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3