Circulating cell-free DNA profiling of patients with advanced urothelial carcinoma

Autor: R.J. Nagy, S. Varambally, Guru Sonpavde, R. Lanman, Amir Ali Talasaz
Rok vydání: 2016
Předmět:
Zdroj: European Journal of Cancer. 60:e5
ISSN: 0959-8049
DOI: 10.1016/j.ejca.2016.03.024
Popis: s / 60 (2016) e1ee19 e5 AOS11. CIRCULATING CELL-FREE DNA PROFILING OF PATIENTS WITH ADVANCED UROTHELIAL CARCINOMA G. Sonpavde*, R.J. Nagy, S. Varambally , R. Lanman, A. Talasaz. University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL, USA. Guardant Health, Inc, Redwood City, CA, USA Background: Circulating cell-free DNA (cfDNA) is obtained noninvasively from peripheral blood and appears to be detectable in most patients with advanced urothelial carcinoma. We report cfDNA profiling of patients with advanced urothelial carcinoma. Methods: 50 patients with urothelial carcinoma that underwent cfDNA analysis using Guardant360 were identified. The 68-gene cfDNA next generation sequencing (NGS) panel from Guardant360 offers complete sequencing for all exons in 29 genes and critical exons in 39 other genes, and copy number amplifications (16), fusions (four), and indels (one) in selected potentially actionable genes harvested from 20 ml of peripheral blood. Findings: Of 50 patients with urothelial carcinoma, cfDNA was detectable in 44 patients (88%). Of these, 39 patients had at least muscle-invasive disease (21 of these had reported metastatic disease) and 11 had no stage information. The most common genes with recurrent somatic mutations in the 44 patients with at least one alteration were TP53 (n Z 26), ARID1A (n Z 10), BRCA2, FGFR2, NF1 (n Z 8 each), BRCA1, CDKN2A, EGFR, PDGFR (n Z 5 each), FGFR3, APC, MET, B-RAF (n Z 4 each), PTEN, ERBB2, K-RAS (n Z 3 each), ALK, GNAS, AR, PIK3CA, NOTCH1, ROS1, ATM, and IDH2 (n Z 2 each). The most common genes with recurrent amplifications were EGFR and ERBB2 (n Z 2 each). Analysis of additional patients is ongoing in this continuously expanding dataset. Interpretation: cfDNA is frequently detected in patients with muscle-invasive and advanced urothelial carcinoma, and alterations appear similar to those reported from urothelial carcinoma tumour tissue. Given that cfDNA offers a non-invasive means of profiling tumour DNA, further development of this promising modality is warranted to guide precision medicine. Additionally, serial cfDNA monitoring may provide insights regarding tumour biology. http://dx.doi.org/10.1016/j.ejca.2016.03.024 AOS12. FUNCTIONAL ACTIVITY OF KINASES IN MUSCLE-INVASIVE BLADDER CANCER TO IDENTIFY POTENTIALLY ACTIONABLE THERAPEUTIC TARGETS G. Sonpavde*, J.C. Anderson, G. Naik, W.E. Grizzle , C.D. Willey. University of Alabama at Birmingham (UAB) Comprehensive Cancer Center, Birmingham, AL, USA. UAB Department of Radiation Oncology, Birmingham, AL, USA. UAB Department of Pathology, Birmingham, AL, USA Background: The Cancer Genome Atlas (TCGA) provided insights into muscle-invasive bladder cancer (MIBC) biology by studying mutations and amplifications in genes, gene expression, andproteins.However, the functional significance of the identified alterations in kinase genes such as those encoding FGFR3, PI3K/AKT/mTOR, and MAPK is unclear. We studied protein kinase activity inMIBC tissue using a novel platform. Methods: We measured kinase activity level using the multiplex substrate microarray PamGene platform (Netherlands) in 24 fresh frozen tissue samples of MIBC and 24 matched adjacent normal bladder tissue samples in patients undergoing radical cystectomy. The PamGene assay measures the ability of lysates from fresh frozen tissue to phosphorylate substrate peptidesandcalculates theupstreamkinases that are functionally active. Kinomic profiling was analysed using software including Evolve (PamGene), and BioNavigator (PamGene) for raw data transformation into kinetic and steady state values. The upstream kinases were identified by using the UpKin PamApp (PamGene) based on the Kinexus database. Clustering of kinases was done in both unpaired and paired manner in cancerous versus healthy tissue specimens. The tumour specimens were compared with matched healthy bladder tissue specimens using the t test. Findings: 23 of 24 patients’ tissue specimens were evaluable since they had acceptable kinase activity. The three kinases with the highest tumour tissue activity (YES1, HCK, and BLK) were all members of the SRC family of tyrosine kinases. Other kinases such as EGFR, PDGFR, CDK1, and PKC also had increased kinase signalling in tumours compared with normal tissue. Among the key functionally activated pathways were RAS, CXCR4, JAK-STAT, CTLA-4, and hyaluronic acid/CD44. Interpretation: In this first innovative study to measure protein kinase activity in MIBC, multiple potential drivers and therapeutic targets were identified. Our data complement studies that measure genomic and transcriptomic kinase alterations and warrant further confirmation to yield therapeutic advances. http://dx.doi.org/10.1016/j.ejca.2016.03.025 AOS13. ANALYSES OF COMBINED PROSTATE CANCER IN RESECTED SPECIMENS BY TOTAL CYSTECTOMY DUE TO URINARY BLADDER CANCER Y. Adachi *, T. Magaribuchi, Y. Nakano, N. Takao, J. Watanabe, T. Shirahase, T. Sakatani , Y. Taki , H. Takeuchi, M. Li, S. Ikehara. Toyooka Hospital, Toyooka, Hyogo, Japan. Kansai Medical University, Hirakata, Osaka, Japan. Hirakata Hospital, Kansai Medical University, Hirakata, Osaka, Japan Background: Presently, malignant tumours are the number one cause of death in Japan, and the number of patients with various cancers is increasing. Prostate cancer is the sixth leading cause of death in men in Japan, with a death rate of 18.9 per 100,000 men. It has been reported that rates in latent prostate cancer are 21.7%, 34.7%, and 50% for men in their 60s, 70s, and 80s or older, respectively. Methods: In this study, we analysed specimens of total cystectomy for evidence of prostate cancer. We focused on 40 cases of total cystectomy at our hospital between 2010 and 2015. The ages of the patients from whom the specimens were obtained ranged from 52 to 92 years (mean 73.5 9.27 years). Findings: 28 (70%) of the 40 cases of total cystectomy showed evidence of prostate cancer. The proportions of patients that underwent cystectomy that were found to also have prostate cancer in the defined age groups (50s, 60s, 70s and 80s and older) were 40% (2/5), 50% (3/6), 75% (15/20), and 89% (8/9), respectively. Interpretation: To our knowledge, the proportion of patients with bladder cancer who also had prostate cancer was high in comparison with any previous data. http://dx.doi.org/10.1016/j.ejca.2016.03.026
Databáze: OpenAIRE
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