Introduction:

Urothelial carcinoma (UC) has a substantial hereditary component. However, the prevalence and potentially heritable mutations that contribute to the development of early onset UC have not been fully elucidated. We evaluate how age of onset could indicate a need for germline mutation testing for detection of inherited form of UC.

Methods:

1536 patients with UC who underwent targeted somatic sequencing on an institutional protocol from October 2015 to July 2020 were included.  Of those, 815 additionally underwent germline testing with a panel of >76 cancer-associated genes. Germline mutation and clinical characteristics were assessed by age of diagnosis of UC. Early onset UC was defined as age of diagnosis of 45 years or younger, which is outside the 95% confidence interval of the median age of UC diagnosis based on SEER analysis. Control cohort was patients with UC diagnosed after 46 years of age. Fisher exact test was used to compare proportions between these cohorts. All statistical computations were performed using STATA version 12.1.

Results:

Of 1536 patients, 80 (5.2%) had early onset UC; Table 1 shows clinical characteristics. Compared to control, early onset cohort had less exposure to tobacco (41 [51.3%] never smoked vs 444 [30.5%], p<0.001) and was more likely to present with low grade UC (12 [15%] vs 64 [4.4%], p<0.001). However, both groups had similar rate of developing metastatic disease (17 [21.3%] vs. 331 [22.7%], p=0.7). Of patients who underwent germline testing (40 [50%] in early onset and 775 [53.2%] in control cohort), early onset was significantly more likely to have any germline mutation (12 [30.0%] vs 116 [15.0%], p=0.02) and clinically significant moderate/high penetrant mutations (10 [25%] vs. 74 [9.5%], p=0.003). The most frequently mutated genes in the early cohort were MSH2 (3/12) and MITF (2/12). Most early onset patients with a germline mutation (11 [91.7%] of 12) presented with UC as their first cancer diagnosis.  

Conclusion:

Clinically significant moderate/high penetrant germline mutations were present in a significant portion of patients with early onset UC in our cohort. Family history alone is not a sensitive criterion to identify patients with potential hereditary UC. Age of onset of 45 years or younger may serve as a useful cutoff when considering referral for genetic counseling/germline mutation testing for patients with potentially hereditary UC.

Funding: NIH T32 Ruth L. Kirschstein Institutional National Research Service Award