Germline variants found in 18% of patients with familial UC


About one in five patients with familial urothelial carcinoma have pathogenic germline variants, according to an analysis of 79 such patients using germline multigene panel testing.

San Francisco-About one in five patients with familial urothelial carcinoma (UC) have pathogenic germline variants, according to an analysis of 79 such patients using germline multigene panel testing.

This incidence is much higher than that reported by The Cancer Genome Atlas (TCGA) consortium, which examined germline variants in patients not selected for family history, said Amin Nassar, MD, who presented his group’s data at the Genitourinary Cancers Symposium in San Francisco.

In the TCGA muscle-invasive bladder cancer dataset, germline pathogenic variants were identified in 30 of 412 patients (7.3%), across 22 genes. A total of 22 of the 30 pathogenic alterations involved DNA damage repair pathway.

“We thought there might be more to the story, especially with the scarcity of information about family history in relation to UC reported in the literature,” said Dr. Nassar, research fellow at Brigham and Women’s Hospital, Boston. “We thought there might be a select population that has a higher prevalence and was worth further study.”

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Two potential cohorts for further study were identified. One group was patients younger than 50 years, “because you would expect that these would have a higher prevalence of germline variants,” he said. “When we looked at the TCGA dataset, we could not find enrichment of germline variants in patients who were younger,” added Dr. Nassar, who worked on the study with Guru P. Sonpavde, MD, and colleagues.

The authors also hypothesized that patients with a family history of UC were a high-risk population and should also be included in the study.

“The reason is that Lynch syndrome is associated with UC, so based on that we thought that patients with family history of UC may be at increased risk for those germline variants and others and thus may be worth studying,” Dr. Nassar said.

His group therefore analyzed patients who had germline multigene panel testing (Invitae) who had a family history of UC, defined as first- to third-degree relatives with UC. Of the 79 patients included, 67 had bladder cancer, six had upper urinary tract cancer, and the site of UC was unknown in six. Six patients were excluded as the relation of the family member was unknown. Forty-eight of the 73 remaining patients (66%) had a first-degree relative with UC and 25 (34%) had a second-degree relative. There were 37 women (51%) and 36 men (49%) in the cohort. Their median age at UC diagnosis was 58 years.

Next: Alterations found in 13 patientsAlterations found in 13 patients

A total of 14 known pathogenic alterations were found in 13 patients (18%). These alterations occurred in SDHC (n=1), MITF (n=2), BRIP1 (n=1), BRCA2 (n=1), MSH2 (n=3), BRCA1 (n=1), CHEK2 (n=1), PTCH (n=1), MUTYH (n=2), and BAP1 (n=1).

Eight of the 48 patients (17%) with first-degree relatives with UC and five of 25 (20%) with second-degree relatives with UC had pathogenic variants. There was no difference in the prevalence of pathogenic variants based on gender (p=.37) or age (p=.77).

CHEK2 has recently been shown to be prominent in other cancers, such as colorectal cancer, and BRCA1/2 variants are prevalent in ovarian and breast cancer. Screening guidelines recommend colonoscopy in patients who have germline CHEK2 variant, and enhanced screening with mammography and breast magnetic resonance imaging for women who have BRCA1 and BRCA2 variants, Dr. Nassar noted.

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Twelve percent of the patients in this study had a variant or alteration in a gene for which the National Comprehensive Cancer Network recommends screening for other cancers, he said.

Immune checkpoint inhibitors are approved therapy by the FDA for patients who have solid tumors with somatic mutations in Lynch syndrome genes. There are no guidelines that recommend immune checkpoint inhibitors as treatment for patients with UC and detected germline variants, “but this could be the subject of further studies in this realm,” said Dr. Nassar. “I also think that with emerging data showing better response to PARP inhibitors in patients with ovarian and breast cancer who have germline BRCA1 or BRCA2 alterations, there is room for potential therapeutic implications in the future.”

Although the high percentage of pathogenic germline variants in UC patients with a family history of UC is intriguing, “It’s too early to recommend a change in guidelines” for this population of patients, he said.

Unpublished data from his group suggest that the prevalence of pathogenic germline variants may be 20% to 30% in patients with UC, “and we are working on expanding our cohort to an unselected UC population,” Dr. Nassar said.

The use of larger gene panels may also provide novel insights, as most patients in the analysis did not have detected pathogenic alterations.

Several of Dr. Nassar’s co-authors have disclosures related to Invitae or pharmaceutical companies. For full disclosures, go to

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