Presentation Authors: Brian Winters*, Navonil De Sarkar, Sonali Arora, Hamid Bolouri, Funda Vakar-Lopez, Heather Cheng, Michael Schweizer, Evan Yu, Lori Kollath, Petros Grivas, Lisa McFerrin, Bruce Montgomery, Jonathan Wright, Hung-Ming Lam, Andrew Hsieh, Seattle, WA
Introduction: Although the genomic landscape of LTUC is well studied, less is known about UTUC, including in the metastatic sites. We evaluated and compared genomic features of metastatic UTUC and LTUC.
Methods: We performed whole exome sequencing on 7 rapid autopsy patients with metastatic UC collected between 2015-2017, with matched primary and metastatic tumor samples (N=37 tumor samples). Single nucleotide variants (SNV) were identified using Mutect and Strelka. Focused analyses were performed on mutations with known significance in UC as well as mutations predicted to have functional impact using a battery of 11 mutation assessors. Genome scale copy number aberrations (CNA) were estimated using Sequenza (normalized for ploidy) to derive gene definition restricted copy number estimation outcomes. Multi-dimensional scaling (MDS) was used to visualize how copy number and high impact, mutation-derived genomic distances differed between and within LTUC and UTUC patients.
Results: We investigated 3 patients with UTUC (3 primary samples, 13 metastases) and 4 patients with LTUC (4 primary samples, 17 metastases). The majority of patients were male (5), non-smokers (4), and received cisplatin-based therapy (5). Pure UC histology was most common with 3 patients having focal squamous cell carcinoma. We found that SNV burden (mean mutation per megabase) was significantly higher in LTUC vs. UTUC overall (6.6 vs. 3.8, p < 0.001) and when stratified by primaries (6.1 vs. 2.9, p=0.03); or metastases (6.7 vs. 4.1, p=0.001). Mutational signature analysis revealed higher proportion of APOBEC signature in all LTUC vs. UTUC tumors. Despite observing a lower overall SNV burden in UTUC, both inter- and intra-individual genomic distances between primary and metastatic tissues were substantially larger in UTUC than LTUC on MDS analysis (Euclidian distance) suggesting a wider spectrum of mutations at the level of individual nucleotides and chromosomal structure. Interestingly, Gene definition-restricted CNA analysis revealed MDM2 amplification exclusively in UTUC tumors which was associated with shallow p53 deletion.
Conclusions: In these patients, metastatic UTUC appears to have a lower overall mutational burden but greater genomic variability compared to LTUC. Our relatively small dataset suggests that metastatic UTUC displays a greater spectrum of mutational divergence from LTUC which may partially explain differences in clinical behavior.
Source of Funding: Howard J Cohen Bladder Cancer Research FoundationJohns Hopkins Greenberg Bladder Cancer Institute