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

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).

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.

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).

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 2015. © 2015 American Cancer Society.

Cancer. 2015 Dec 09 [Epub ahead of print]

Jeffrey S Ross, Kai Wang, Depinder Khaira, Siraj M Ali, Huge A G Fisher, Badar Mian, Tipu Nazeer, Julia A Elvin, Norma Palma, Roman Yelensky, Doron Lipson, Vincent A Miller, Philip J Stephens, Vivek Subbiah, Sumanta K Pal

Department of Pathology and Laboratory Medicine, Albany Medical College Albany, New York. , Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts. , Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts. , Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts. , Department of Pathology and Laboratory Medicine, Albany Medical College Albany, New York. , Department of Pathology and Laboratory Medicine, Albany Medical College Albany, New York. , Department of Pathology and Laboratory Medicine, Albany Medical College Albany, New York. , Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts. , Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts. , Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts. , Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts. , Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts. , Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts. , Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. , Department of Medical Oncology and Experimental Therapeutics, City of Hope Cancer Center, Duarte, California. 

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