Response to K. Hemminki et al.

Our research team acknowledges some of the limitations highlighted by Hemminki and colleagues (specifically the low prevalence of variant histology and the weak impact of smoking), which we previously addressed in our article. The purpose of our study was to better characterize the pattern of familial cancer risk (both concordant and discordant) in relatives of urothelial cancer patients. This is part of a larger goal of defining a phenotype of cancer across anatomic sites that includes bladder cancer. Central to this work is making analytic decisions that reduce phenotypic heterogeneity, such as excluding variant histology. Squamous cancer is remarkably distinct in its biology, epidemiology, and treatment. While the relative frequency of squamous cell carcinoma is low, and therefore does not drive the observed associations, removing it allows us to refine this phenotypic definition. To do this, we excluded 6462 individuals from the analysis: 1869 individuals with a bladder cancer diagnosis that was not the first primary, 368 individuals with nonurothelial bladder cancer, 4217 individuals with kidney and renal cancer, and eight ureteral cases.

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