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Sources of Funding: Kleberg Center for Molecular Markers and the Institute for Personalized Cancer Therapy; Eleanor and Scott Petty Fund for Study of Upper Tract Urothelial Carcinoma; Monteleone Family Foundation for Research in Bladder and Kidney Cancers.

Introduction

Upper urinary tract urothelial cancer has many similarities to lower urinary tract cancer but also has many unique etiologic and genomic factors. We performed a comprehensive integrated genomic analysis of UTUC in order to characterize the genomic landscape of UTUC and provide insights into biology.

Methods

We obtained 31 untreated fresh snap frozen UTUCs under approved IRB approved protocols from 2 academic institutions. Following histologic confirmation and quality control for adequate viable tumor, DNA, RNA and protein underwent WES, RNAseq, and RPPA analysis. After adjusting for batch effects, consensus mutation calls from independent pipelines from each center identified gene expression clusters using unsupervised consensus hierarchical clustering (UCHC).

Results

Clinical data are shown in the Table. WES identified mutations in FGFR3 (74.1%), enriched not only in low grade tumors (92%), but also high grade (60%); KMT2D (44.4%), PIK3CA (25.9%), TP53 (22.2%). APOBEC and CpG signatures were identified. UCHC of RNAseq segregated samples into 4 molecular subtypes, not all of which resembled bladder TCGA subtypes. Cluster 1: no PIK3CA mutations; enriched for nonsmokers, high grade non-muscle invasive tumors, high recurrence rates and favorable survival. Cluster 2: 100% FGFR3 mutations; enriched for low grade, noninvasive disease, no bladder recurrences. Cluster 3: 100% FGFR3 mutations, 71% PIK3CA, no TP53 mutations; high tobacco use and bladder recurrence (62.5%); tumors all non-muscle invasive. Cluster 4: KMT2D (62.5%), FGFR3 (50%), TP53 (50%) mutations, no PIK3CA mutations; enriched for high grade, muscle-invasive disease, tobacco use, CIS, reduced survival; novel fusion of SH3KBP1-CNTNAP5 was identified, with high expression levels in the sample.

Conclusions

We show mutations in UTUC occurring at differing frequencies and subtypes that differ from high grade invasive bladder cancer. Novel fusion SH3KBP1 regulates RTK signaling and acts to recycle TGF? receptors. Further studies are needed to validate the described subtypes, explore their responses to therapy, and better define the novel fusion mutation.

Funding

Kleberg Center for Molecular Markers and the Institute for Personalized Cancer Therapy; Eleanor and Scott Petty Fund for Study of Upper Tract Urothelial Carcinoma; Monteleone Family Foundation for Research in Bladder and Kidney Cancers.