Genomic landscape of locally advanced or metastatic urothelial carcinoma with squamous differentiation compared to pure urothelial carcinoma.
Bladder cancer
Chromatin remodeling
KMT2D
Squamous differentiation
Urothelial carcinoma
Journal
Urologic oncology
ISSN: 1873-2496
Titre abrégé: Urol Oncol
Pays: United States
ID NLM: 9805460
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
received:
10
04
2022
revised:
01
06
2022
accepted:
04
07
2022
pubmed:
3
8
2022
medline:
26
10
2022
entrez:
2
8
2022
Statut:
ppublish
Résumé
Urothelial carcinoma with squamous differentiation (UCS) is the most common variant differentiation of urothelial carcinoma (UC). Although treatment is usually similar to pure UC, there is paucity of data regarding its genomic landscape and putative molecular drivers. In this study, we compared the mutational profile of tumors with UCS and UC histology. In this IRB-approved retrospective study, patients with advanced UCS and UC undergoing tumor based comprehensive genomic profiling from a CLIA-certified laboratory were included. An independent genitourinary pathologist reviewed all cases. Patients were determined to have UCS based on presence of any component of squamous differentiation. Patients with UC having any other secondary histology variant were excluded. Genes with alterations (GA) in less than 5% of patients and variants of unknown significance were excluded from the analysis. Chi-square test was used to compare gene aberration frequency and the p-values were adjusted for false using Benjamini-Hochberg (BH) correction. Among the 87 eligible patients with UCS (n=31) and UC (n=56), patients with UCS were more likely to be female (32.3% vs. 14.3%, p=0.047) with no significant differences in other clinicopathological features. Most common genomic alterations seen in UCS were TP53 (67.7%), KMT2D (48.4%) and ARID1A (32.3%). KMT2D mutations were significantly enriched in UCS (48.4% vs. 0%, FDR adj p <0.001, p = <0.001) compared to UC. Prevalence of CUL4A mutations was numerically higher in UCS vs. UC (12.9% vs. 1.8%, FDR adj p = 0.43, p = 0.03). Tumor mutation burden and the number of genomic aberrations per patient were not significantly different between the two groups. These findings highlight significant enrichment of KMT2D mutations in UCS and potential role of chromatin remodeling genes as drivers and potential therapeutic targets.
Sections du résumé
BACKGROUND
Urothelial carcinoma with squamous differentiation (UCS) is the most common variant differentiation of urothelial carcinoma (UC). Although treatment is usually similar to pure UC, there is paucity of data regarding its genomic landscape and putative molecular drivers. In this study, we compared the mutational profile of tumors with UCS and UC histology.
METHODS
In this IRB-approved retrospective study, patients with advanced UCS and UC undergoing tumor based comprehensive genomic profiling from a CLIA-certified laboratory were included. An independent genitourinary pathologist reviewed all cases. Patients were determined to have UCS based on presence of any component of squamous differentiation. Patients with UC having any other secondary histology variant were excluded. Genes with alterations (GA) in less than 5% of patients and variants of unknown significance were excluded from the analysis. Chi-square test was used to compare gene aberration frequency and the p-values were adjusted for false using Benjamini-Hochberg (BH) correction.
RESULTS
Among the 87 eligible patients with UCS (n=31) and UC (n=56), patients with UCS were more likely to be female (32.3% vs. 14.3%, p=0.047) with no significant differences in other clinicopathological features. Most common genomic alterations seen in UCS were TP53 (67.7%), KMT2D (48.4%) and ARID1A (32.3%). KMT2D mutations were significantly enriched in UCS (48.4% vs. 0%, FDR adj p <0.001, p = <0.001) compared to UC. Prevalence of CUL4A mutations was numerically higher in UCS vs. UC (12.9% vs. 1.8%, FDR adj p = 0.43, p = 0.03). Tumor mutation burden and the number of genomic aberrations per patient were not significantly different between the two groups.
CONCLUSION
These findings highlight significant enrichment of KMT2D mutations in UCS and potential role of chromatin remodeling genes as drivers and potential therapeutic targets.
Identifiants
pubmed: 35918248
pii: S1078-1439(22)00257-5
doi: 10.1016/j.urolonc.2022.07.002
pii:
doi:
Substances chimiques
CUL4A protein, human
0
Cullin Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
493.e1-493.e7Informations de copyright
Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Conflict of interest Neeraj Agarwal reports consultancy to Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. His institution receives research funding from Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. Umang Swami reports consultancy to Astellas, Exelixis and Seattle Genetics and research funding to institute from Janssen, Exelixis and Astellas/Seattle Genetics. Abhishek Tripathi reports consultancy to Foundation Medicine, Pfizer, Genzyme, EMD Sorono, Exelixis, Deka Biosciences, Seattle Genetics, Urology Times honorarium), Cardinal health (honorarium). His institution receives research funding from Clovis Oncology, Corvus Pharmaceuticals, Bayer, EMD Serono, Aravive, WindMIL, Exact Sciences, Pfizer. Benjamin Haaland reports consultancy to Value Analytics and the National Kidney Foundation. Sumati Gupta reports research funding from BMS, Rexahn, Incyte, Novartis, LSK, Five Prime, Mirati, QED, Debiopharm, Merck, Pfizer, Astra Zeneca, MedImmune, Clovis; travel fund from QED; spouse has stock ownership in Salarius Pharmaceuticals. Benjamin Maughan reports consultancy to Abbive, Pfizer, AVEO oncology, Janssen, Astellas, Bristol-Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology and Peloton Therapeutics. His institution receives research funding from Exelixis, Bavarian-Nordic, Clovis, Genentech and Bristol-Myers Squibb. Petros Grivas reports consulting fees from AstraZeneca, Astellas Pharma, Bayer, Bristol Myers Squibb, Dyania Health, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, Genzyme, GlaxoSmithKline, Guardant Health, Gilead Sciences, Infinity Pharmaceuticals, Janssen, Merck, Mirati Therapeutics, Pfizer, QED Therapeutics, Regeneron Pharmaceuticals, Seattle Genetics, UroGen, SilverBack Therapeutics, 4D Pharma PLC. His institution has received grants from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm, EMD Serono, GlaxoSmithKline, Gilead Sciences, Merck, Mirati Therapeutics, Pfizer, QED Therapeutics, G1 Therapeutics. Roberto Nussenzveig has consulted for Tempus, Nishita Tripathi, Yeonjung Jo, Nicolas Sayegh, Haoran Li, Vinay Mathew Thomas, Sumanta Pal and Deepika Sirohi have no conflict of interest to disclose.