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Updated: Aug 29, 2025
Cell-Free DNA Integrity Analysis in Urine Samples
Published on: January 5, 2017
Comprehensive Landscape of Cyclin Pathway Gene Alterations and Co-occurrence with FGF/FGFR Aberrations Across Urinary
Denis L F Jardim1,2, Sherri Z Millis3, Jeffrey S Ross3,4
1Department of Clinical Oncology, Hospital Sirio Libanes, São Paulo, Brazil.
Background:
Cyclin pathway gene alterations are frequent in urothelial tumors and may co-exist with other important aberrations, leading to therapeutic opportunities. We characterized the landscape of cyclin gene alterations in urothelial and non-urothelial urinary tract (UT) malignancies.
Patients And Methods:
Overall, 6842 urothelial and 897 non-urothelial UT cancers were analyzed (hybrid-capture-based comprehensive genomic profile (Foundation Medicine)). Alteration frequency in cyclin-sensitizing and -resistance genes, and co-occurrence with fibroblast growth factor receptor (FGFR) gene abnormalities were evaluated.
Results:
Cyclin-activating gene alterations were detected in 47.3% of urothelial and 37.9% of non-urothelial UT cancers. Frequency varied by histology and tumor site. CDKN2A and CDKN2B loss were the most frequent alterations in urothelial tumors (present in 38.5% and 30.4% of patients, respectively). Both genes were less frequently altered in adenocarcinomas (15.2% and 8.9%), but commonly altered in squamous cell carcinomas (74.4% and 39%). Tumors of neuroendocrine origin were relatively silent in activating cyclin alterations, but frequently displayed Rb1 alterations (86% and 83.7% of neuroendocrines and small cell carcinomas). Urachal tumors (n = 79) presented a distinct landscape of cyclin alterations relative to other UT cancers, with less frequent alterations overall. FGF/FGFR genes were altered in 34.9% of urothelial (22.1% in FGFR3), and 19.4% of non-urothelial urinary tract tumors (6.8% FGFR3). Cyclin-activating alterations frequently co-occurred with FGF/FGFR alterations but were in general mutually exclusively with cyclin resistance alterations (RB1/CCNE1).
Conclusions:
Cyclin pathway activating alterations are common in urinary tract tumors, but frequency varies with histology and tumors sites. Co-occurrence of cyclin and FGFR pathway alterations may inform therapeutic opportunities.
Insights
Cyclin pathway gene alterations are common in urinary tract cancers, varying by histology and site. Co-occurrence with FGFR alterations presents therapeutic opportunities for these malignancies.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Cyclin pathway gene alterations are prevalent in urothelial tumors.
- These alterations can coexist with other genetic abnormalities, offering potential therapeutic targets.
- Characterizing the spectrum of cyclin gene alterations in urinary tract malignancies is crucial.
Purpose of the Study:
- To investigate the landscape of cyclin gene alterations in urothelial and non-urothelial urinary tract cancers.
- To evaluate the frequency of alterations in cyclin-sensitizing and -resistance genes.
- To assess the co-occurrence of cyclin gene alterations with fibroblast growth factor receptor (FGFR) gene abnormalities.
Main Methods:
- Analysis of 6842 urothelial and 897 non-urothelial urinary tract cancers.
- Utilized hybrid-capture-based comprehensive genomic profiling data.
- Examined alteration frequencies and co-occurrence patterns with FGFR and cyclin resistance genes.
Main Results:
- Cyclin-activating alterations were found in 47.3% of urothelial and 37.9% of non-urothelial UT cancers, with frequencies varying by histology and tumor site.
- CDKN2A and CDKN2B loss were most frequent in urothelial tumors but less common in adenocarcinomas and frequent in squamous cell carcinomas.
- FGF/FGFR genes were altered in 34.9% of urothelial and 19.4% of non-urothelial UT tumors; cyclin-activating alterations frequently co-occurred with FGF/FGFR alterations.
Conclusions:
- Activating cyclin pathway alterations are common in urinary tract tumors, with significant variation based on histology and tumor site.
- The co-occurrence of cyclin and FGFR pathway alterations provides insights into potential therapeutic strategies.
- Understanding these genetic landscapes is key for developing targeted treatments for urinary tract cancers.
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