Evaluation of Clinically Actionable Germline Pathogenic Variants in UTUC

Sumati Gupta, MD, and Wendy Kohlmann, MS, discuss how certain cancer sites, like the urethra and upper tract, have a higher prevalence of pathogenic variants, as well as why comprehensive germline testing is crucial for accurate diagnosis and treatment.

View their continued comments on the Impact of Disease Site on Germline Variants in Urinary Tract Cancer.

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Can you share the inspiration for your research? Why were patients with UTUC enrolled for molecular testing of their germline and tumor, and why did you decide to evaluate factors that could affect the likelihood of finding a pathogenic variant?

Ms. Kohlmann: The idea for this project was largely driven by Dr. Gupta, who was seeing patients with urothelial cancer in her practice. She noticed that many had significant personal or family histories of cancer, but there were limited guidelines on when to pursue germline genetic testing for these cancer types. This observation led to a collaboration between Dr. Gupta, myself, and the genetic counseling team to explore the issue further.

We utilized the Orion Avatar program, which is part of a network of cancer centers enrolling patients in a centralized protocol. The Avatar project, one of its main initiatives, conducts whole exome sequencing of both germline and tumor DNA. This provided a diverse dataset of patients who were enrolled prospectively, without being selected for high risk. It was an excellent resource for studying the factors that could predict which urothelial cancer patients might have underlying germline pathogenic variants.

Dr. Gupta: We know that aging, smoking, and other carcinogenic exposures are the primary risk factors for urothelial cancer. There is also a familial component, which may be due to shared environmental risks or genetic predisposition. Published evidence in select populations with urothelial cancers has identified germline variants in 11% to 24% of patients. Most studies have shown a higher prevalence of homologous recombination repair gene mutations compared to mismatch repair gene mutations, which are classically associated with Lynch syndrome. Current guidelines recommend evaluating genetic risk in patients who are younger or have risk factors for Lynch syndrome, but we are not sure these guidelines are sufficient to identify all patients with inherited cancer syndromes.

The main aim of our study was to identify clinical features associated with inherited cancer predisposition syndromes in urothelial cancer patients. We chose to analyze the Orion dataset because these patients were not selected based on inherited risk; they represent a real-world population of patients diagnosed with urothelial cancer at various cancer institutes across the U.S.

Please explain the design and methodology of your analysis. How were clinically actionable germline pathogenic variants in cancer predisposition genes identified, and what kind of analyses were conducted?

Ms. Kohlmann: Through the Orion dataset, we had access to patients with confirmed diagnoses of urothelial cancer who had also completed germline exome sequencing. This included research-grade exome sequencing and molecular testing of their tumors. We selected patients with complete datasets and aimed to compare those with germline pathogenic variants to those without, in order to identify factors associated with having a germline variant. A key part of our study design involved deciding how to classify pathogenic variants. While exome sequencing allowed us to identify various types of genetic variants, we focused our analysis on individuals with known pathogenic variants in genes associated with an increased cancer risk in heterozygotes.

We concentrated on genes known to confer clinically actionable cancer risks and variants already classified as pathogenic in ClinVar. While we have further analyses planned to explore more novel associations, for this analysis, we applied stringent criteria to ensure we focused on variants with an established connection to cancer risk. This served as the basis for defining our two comparison groups.

Dr. Gupta: We selected patients diagnosed with urothelial cancer who had germline genomic data available and examined various clinical and disease features to identify those associated with inherited risk. We believed that identifying factors linked to inherited cancer syndromes could help clinicians recognize patients who should undergo genetic testing. After identifying patients with pathogenic germline variants, we analyzed their clinical and tumor characteristics. The dataset provided detailed information, such as the primary site of disease, age at diagnosis, and disease stage. We also assessed tumor genomic features, including microsatellite instability, loss of heterozygosity, and tumor mutational burden. Additionally, for tumors with available RNA-seq data, we were able to perform cluster classification.