University Hospital del Mar, IMIM, Barcelona, Spain
Joaquim Bellmunt , Guangwu Guo , Stephanie A. Mullane , Anna Orsola , Lillian Werner , Paul Van Hummelen , Aaron Thorner , Massimo Loda , Toni K. Choueiri , Justine A. Barletta , David J. Kwiatkowski , Matthew Meyerson , Eliezer Mendel Van Allen
Background: The genomic landscape of high-grade T1 micropapillary bladder tumors (HGT1micropap) is unknown. Clinically, micropapillary bladder cancer is an aggressive and possibly lethal disease. Our main objective was to assess the genomic landscape of HGT1micropap through identifying mutations, insertions/deletions (indels), translocations, and copy number variations (CNVs). Methods: We prospectively identified nine HGT1micropap with 45.4 months of median follow up. Patients were treated in a uniform manner using TUR, BCG, and appropriate follow up. We performed whole exome sequencing using Ilumina Exome _v5 plus translocation. Mutations and indels were called using the Firehose pipeline. CNVs were called using ExomeCNV. We examined the mutational landscape and compared the genomic alterations to TCGA (>T2, n=131)2 and publicly available data on non-muscle invasive bladder tumors (Ta/T1, n=37)1. Results: Within the HGT1micropap, mutations on TP53, KMT2D, TSC1, and ATM were suggested to occur more frequently compared to the NMIBC control group1. FGFR3 was seen at the expected frequency for NMIBC. The mutations of interest are presented in Table 1 with the percentage seen in the other cohorts. Of interest, TSC1 was seen in higher frequency in micropapillary than in the NMIBC or the TCGA cohort2. We did not see any patterns between CNVs and mutations. We also saw two patients with severe chromothripsis. 3 patients had loss of chromosome 9 or 9q without any other severe chromosome alterations. CNV alterations will be presented and compared to MIBC. Conclusions: In this preliminary analysis, our HGT1micropap, showed a mutational landscape more similar to MIBC compared to NMIBC bladder landscape. We did not find any clear driver of the micropapillary histology at the exome level in this limited sample of patient, which may indicate that tumor heterogeneity or epigentic changes may be driving this aggressive phenotype.
Gene | TCGA (%) | HGT1micropap | Ta/T1 (%) |
---|---|---|---|
TP53 | 49% | 5/9 | 24% |
KMT2D | 24% | 3/9 | 3% |
TSC1 | 8% | 2/9 | 8% |
ATM | 15% | 3/9 | 5% |
FGFR3 | 12% | 3/9 | 27% |
FOXA1 | 5% | 2/9 | 0% |
RB1 | 13% | 2/9 | 11% |
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