(UroToday.com) The 2024 IBCN annual meeting included a session on preclinical models and genomic insights, featuring a presentation by Dr. Philippe Lamy discussing the comprehensive genomic characterization of early stage bladder cancer. Most patients with non-muscle invasive bladder cancer (NMIBC) have a good prognosis, but up to 40% progress to muscle invasive bladder cancer within 5 years, depending on the clinical risk group. Identifying patients likely to progress is critical to provide optimal treatment strategies. With the aim of improving our understanding of disease aggressiveness, Dr. Lamy and colleagues present the largest multi-omics study on NMIBC to date.
This study included a comprehensive genomic characterization of tumors from 438 patients with NMIBC from the European UROMOL consortium (n = 296) and from Aarhus University Hospital, Denmark (n = 142). The methods and sequencing strategy is as follows:
Whole exome sequencing (n = 438) was performed on paired tumor and germline DNA supplemented by shallow whole genome sequencing (n = 362) on tumor samples only. Total RNA- sequencing data was generated earlier (n = 414).
Sixty genes were significantly mutated in NMIBC, with FGFR3 (59%), KDM6A (43%), and KMT2D (37%) being most frequent. The investigators identified a large genomic variation within NMIBC with FGFR3, KMT2D, and STAG2 being more frequently mutated in UROMOL2021 class 1 and 3 tumors, while class 2a tumors had frequent TP53, ARID1A, and RB1 mutations, similarly to muscle invasive bladder cancer. There was no specific mutation enriched in class 2b. There was frequent copy neutral loss of heterozygosity in FGFR3 and frequent arm-level loss of heterozygosity of 17p (affecting TP53) in tumors with co-occurring mutations in FGFR3 and TP53, respectively. Whole-genome doubling was observed in 15% of the tumors and was associated with an increased risk of progression, a higher mutation load, and frequent alterations in genes related to cell-cycle regulation:
Whole-genome doubling tumors had an altered immune composition with higher scores for neutrophils and T-cell exhaustion. Additionally, Dr. Lamy and colleagues applied integrative clustering analysis of somatic mutations, copy number alterations, and gene expression data for 230 tumors to encapsulate the underlying biology of disease aggressiveness in NMIBC:
They found that both genomic instability, transcriptomic subtype scores, and the functional status of infiltrating immune cells were associated with clinically high-risk tumors beyond whole-genome doubling status. The following summarizes iClus1/iClus 3, iClus 4, and iClus2:
Dr. Lamy concluded his presentation by discussing the comprehensive genomic characterization of early stage bladder cancer with the following take-home points:
- This a new genomic layer on the UROMOL cohort
- There are 33 genes that are significant and recurrence (>5% of samples) – the mutational landscape is different for each transcriptomics class
- 15% of samples have WGD (compared to 58% for muscle invasive bladder cancer)
- WGD is associated with bad outcomes, cell cycle checkpoint pathways, and specific immune context
- iClus4 comprises a group of highly aggressive tumors and provides a better stratification than transcriptomic subtype alone
Presented by: Philippe Lamy, PhD, Aarhus University Hospital, Aarhus, Denmark
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 International Bladder Cancer Network (IBCN) Annual Meeting, Bern, Switzerland, Thurs, Sept 19 – Sat, Sept 21, 2024.