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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 01; 122(5):702-11.C

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.

Authors+Show Affiliations

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 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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26651075

Citation

Ross, Jeffrey S., et al. "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, vol. 122, no. 5, 2016, pp. 702-11.
Ross JS, Wang K, Khaira D, et al. 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;122(5):702-11.
Ross, J. S., Wang, K., Khaira, D., Ali, S. M., Fisher, H. A., Mian, B., Nazeer, T., Elvin, J. A., Palma, N., Yelensky, R., Lipson, D., Miller, V. A., Stephens, P. J., Subbiah, V., & Pal, S. K. (2016). 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, 122(5), 702-11. https://doi.org/10.1002/cncr.29826
Ross JS, et al. 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. PubMed PMID: 26651075.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. AU - Ross,Jeffrey S, AU - Wang,Kai, AU - Khaira,Depinder, AU - Ali,Siraj M, AU - Fisher,Huge A G, AU - Mian,Badar, AU - Nazeer,Tipu, AU - Elvin,Julia A, AU - Palma,Norma, AU - Yelensky,Roman, AU - Lipson,Doron, AU - Miller,Vincent A, AU - Stephens,Philip J, AU - Subbiah,Vivek, AU - Pal,Sumanta K, Y1 - 2015/12/09/ PY - 2015/06/05/received PY - 2015/08/19/revised PY - 2015/08/24/accepted PY - 2015/12/10/entrez PY - 2015/12/10/pubmed PY - 2016/7/9/medline KW - bladder cancer KW - comprehensive genomic profiling KW - cyclin-dependent kinase inhibitor 2A (CDKN2A) KW - fibroblast growth factor receptor (FGFR) KW - metastatic KW - micropapillary SP - 702 EP - 11 JF - Cancer JO - Cancer VL - 122 IS - 5 N2 - 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. SN - 1097-0142 UR - https://www.unboundmedicine.com/medline/citation/26651075/Comprehensive_genomic_profiling_of_295_cases_of_clinically_advanced_urothelial_carcinoma_of_the_urinary_bladder_reveals_a_high_frequency_of_clinically_relevant_genomic_alterations_ L2 - https://doi.org/10.1002/cncr.29826 DB - PRIME DP - Unbound Medicine ER -