Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma.

TitleComprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma.
Publication TypeJournal Article
Year of Publication2017
AuthorsMoss, TJ, Qi, Y, Xi, L, Peng, B, Kim, T-B, Ezzedine, NE, Mosqueda, ME, Guo, CC, Czerniak, BA, Ittmann, M, Wheeler, DA, Lerner, SP, Matin, SF
JournalEur Urol
Date Published2017 10
KeywordsAged, Aged, 80 and over, Biomarkers, Tumor, Cluster Analysis, Computational Biology, Databases, Genetic, DNA Mutational Analysis, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genomics, Humans, Kidney Neoplasms, Kidney Pelvis, Male, Multigene Family, Mutation, Mutation Rate, Phenotype, Sequence Analysis, Protein, Sequence Analysis, RNA, Texas, Treatment Outcome, Ureter, Ureteral Neoplasms, Urinary Bladder Neoplasms, Urothelium, Whole Exome Sequencing

BACKGROUND: Upper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer.

OBJECTIVE: To characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses.

DESIGN, SETTING, AND PARTICIPANTS: We collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adjusting for batch effects, consensus mutation calls from independent pipelines identified DNA mutations, gene expression clusters using unsupervised consensus hierarchical clustering (UCHC), and protein expression levels that were correlated with relevant clinical variables, The Cancer Genome Atlas, and other published data.

RESULTS AND LIMITATIONS: WES identified mutations in FGFR3 (74.1%; 92% low-grade, 60% high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). APOBEC and CpG were the most common mutational signatures. UCHC of RNAseq data segregated samples into four molecular subtypes with the following characteristics. Cluster 1: no PIK3CA mutations, nonsmokers, high-grade

CONCLUSIONS: Mutations in UTUC occur at differing frequencies from bladder cancer, with four unique molecular and clinical subtypes. A novel SH3KBP1 fusion regulates RTK signaling. Further studies are needed to validate the described subtypes, explore their responses to therapy, and better define the novel fusion mutation.

PATIENT SUMMARY: We conducted a comprehensive study of the genetics of upper urinary tract urothelial cancer by evaluating DNA, RNA and protein expression in 31 tumors. We identified four molecular subtypes with distinct behaviors. Future studies will determine if these subtypes appear to have different responses to treatments.

Alternate JournalEur Urol
PubMed ID28601352

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