Impact of Disease Site on Germline Variants in Urinary Tract Cancer

Sumati Gupta, MD, and Wendy Kohlmann, MS, continue their discussion with a focus on the difference in prevalence of pathogenic variants between patients with primary disease sites in the urethra, upper tract, and bladder.

View their previous comments on Evaluation of Clinically Actionable Germline Pathogenic Variants in UTUC.

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How did the prevalence of pathogenic variants differ between patients with primary disease sites in the urethra, upper tract, and bladder?

Ms. Kohlmann: Germline pathogenic variants were found more frequently in individuals with upper tract urothelial cancer, which is consistent with other studies showing similar results. However, we did not observe any other statistically significant differences between the two groups in terms of demographics, clinical characteristics, or family history. As a genetic counselor, I was particularly interested in the family history data.

The family history information we had through the Orion dataset was somewhat limited. We broadly classified the two groups as having a family history of cancer in close relatives versus not. It is possible that with more detailed family history information, we might have observed differences in the strength of family history or the types of cancers.

However, the family history we had was abstracted from medical records and generally reflects the type of information collected during routine clinical care. So, it is certainly possible that we missed an association between family history and pathogenic variants. Our study, like many others, found that family history alone is not always sufficient to identify all patients who may have underlying germline pathogenic variants.

Dr. Gupta: The bladder is the most common site of urothelial cancer, with only a minority of patients presenting with disease in the upper tract or urethra. Comprehensive germline panel testing could help identify inherited cancer syndromes in the small subset of patients with non-bladder primary sites.

What proportion of the identified pathogenic variants were in homologous recombination repair genes, mismatch repair genes, and other pathways?

Ms. Kohlmann: Lynch syndrome is the hereditary condition most strongly associated with an increased risk of urothelial cancer. However, in our dataset, 60% of the mutations were in homologous recombination repair genes. Another 19% were in genes from other pathways, and 19% were in mismatch repair genes. So, Lynch syndrome accounted for only a minority of the genetic findings among those with actionable pathogenic variants.

While our analysis was not designed to prove that these other genes necessarily confer an increased risk, as Dr. Gupta mentioned, other studies have shown similar results; many different genes may be involved, or patients may harbor pathogenic variants in them.

This idea of using microsatellite instability or a family history of Lynch syndrome-related cancers as the primary criteria for identifying people who would benefit from genetic testing will miss the majority of individuals with actionable germline variants. I believe this provides further evidence that we need to take a broader approach and test more widely in these patients.

Dr. Gupta: Our study shows that by focusing on patients with non-bladder primary sites of disease and performing comprehensive panel testing, we may identify a clinically actionable inherited risk in 11% of cases.

What further research do you believe is necessary regarding germline and tumor molecular testing in patents with urinary tract cancer?

Ms. Kohlmann: Our findings do support the idea that some of these patients warrant germline testing, and this will become increasingly indicated for them.

As a genetic counselor, I feel like this is one of many studies showing that the prevalence of germline pathogenic variants in cancer patients is higher than we previously realized, and that we need to broaden our testing approach. I believe Dr. Gupta will speak more to our future research goals in urothelial cancer specifically.

But from a genetic counseling perspective, this is further evidence that we need to pair these studies with implementation science projects. It is crucial to develop automated tools to help us identify patients diagnosed with cancers that warrant genetic testing, and to ensure we have the resources to reach out efficiently and offer them germline testing. This research is expanding the scope of patients who should be considered for genetic testing.

At the Huntsman Cancer Institute, we have several studies underway that focus on this implementation aspect. I believe this is a critical area of focus, as it is necessary to complement these research findings with actionable steps. We need practical tools to ensure genetic counseling and testing are accessible to the patients who need them.

Dr. Gupta: In terms of further research, we continue to analyze the growing Orion dataset. We are looking to identify novel germline variants associated with urothelial cancer susceptibility. We are also exploring the role of germline makeup in tumor biology, combining germline molecular data with tumor molecular profiles and clinical disease scores. This will help us move toward more precise and personalized treatments for urothelial cancer.