Familial Cancer Clustering in Urothelial Cancer: A Population-Based Case–Control Study

Abstract

Background: Family history of bladder cancer confers an increased risk for concordant and discordant cancers in relatives. However, previous studies investigating this relationship lack any correction for smoking status of family members. We conducted a population-based study of cancer risks in relatives of bladder cancer patients and matched controls with exclusion of variant subtypes to improve the understanding of familial cancer clustering. Methods: Case subjects with urothelial carcinoma were identified using the Utah Cancer Registry and matched 1:5 to cancerfree controls from the Utah Population Database. Cox regression was used to determine the risk of cancer in first-degree relatives, second-degree relatives, first cousins, and spouses. A total of 229 251 relatives of case subjects and 1 197 552 relatives of matched control subjects were analyzed. To correct for smoking status, we performed a secondary analysis excluding families with elevated rates of smoking-related cancers. All statistical tests were two-sided. Results: First-and second-degree relatives of case subjects had an increased risk for any cancer diagnosis (hazard ratio [HR] ¼ 1.06, 95% confidence interval [CI] ¼ 1.03 to 1.09, P < .001; HR ¼ 1.04, 95% CI ¼ 1.02 to 1.07, P ¼ .001) and urothelial cancer (HR ¼ 1.73, 95% CI ¼ 1.50 to 1.99, P < .001; HR ¼ 1.35, 95% CI ¼ 1.21 to 1.51, P < .001). Site-specific analysis found increased risk for bladder (HR ¼ 1.69, 95% CI ¼ 1.47 to 1.95, P < .001), kidney (HR ¼ 1.30, 95% CI ¼ 1.08 to 1.57, P ¼ .006), cervical (HR ¼ 1.25, 95% CI ¼ 1.06 to 1.49, P ¼ .01), and lung cancer (HR ¼ 1.34, 95% CI ¼ 1.19 to 1.51, P < .001) in first-degree relatives. Second-degree relatives had increased risk for bladder (HR ¼ 1.35, 95% CI ¼ 1.2 to 1.5, P < .001) and thyroid cancer (HR ¼ 1.18, 95% CI ¼ 1.03 to 1.35, P ¼ .02). Spouses showed an increased risk for laryngeal (HR ¼ 2.68, 95% CI ¼ 1.02 to 7.05, P ¼ .04) and cervical cancer (HR ¼ 1.57, 95% CI ¼ 1.13 to 2.17, P ¼ .007). These results did not substantively change after correction for suspected smoking behaviors. Conclusion: Our results suggest familial urothelial cancer clustering independent of smoking, with increased risk in relatives for both concordant and discordant cancers, suggesting shared genetic or environmental roots. Identifying families with statistically significant risks for non-smoking-related urothelial cancer would be extremely informative for genetic linkage studies.

Redefining the Bladder Cancer Phenotype using Patterns of Familial Risk

“…Sixteen cancer-types previously shown to be associated with BCa (thyroid, leukemia, pancreas, brain/CNS, lung, stomach, liver, larynx, melanoma, prostate, breast, ovarian, kidney, myeloma, small intestine, and ocular) (1, 14), plus BCa (17 cancers total) were considered simultaneously.…”

“…The following histologies were not included (8000, 8001, 8010, 8041, 8120, 8122, 8130, 8140, 8211, 8249, and 8255) (1). Enrichment was measured as a binary variable, (1= Yes, statistically higher level of cancer than the general population; 0=No).…”

“…Relatives of bladder cancer (BCa) patients are at increased risk for kidney, lung, thyroid, and cervical cancer after correcting for smoking related behaviors (1)(2)(3)(4). Family history is an important risk factor for many cancers, which may extend across cancer types (5,6).…”

Bladder cancer risk associated with family history of cancer

“…3,4 Case-control and family-based studies have estimated that those with a family history of bladder cancer are approximately twice as likely to develop bladder cancer. [5][6][7][8][9][10][11][12] Several elements of this increased familial risk for bladder cancer are not well understood. Some epidemiologic studies have implicated higher risks for bladder cancer among different relatives including parents [7][8][9]12 and siblings (especially brothers).…”

RE: Familial Cancer Clustering of Urothelial Cancer: A Population-Based Case–Control Study

“…Martin and coworkers reported data on familial associations of urothelial cancers (n ¼ 7266) with urothelial cancers and with other (discordant) cancers based on the Utah Population Database, asserting novelty in being able to control for smoking and histology (1). Studies with multiple discordant cancers are subject to chance findings, but the authors guarded against these by assessing consistency of the findings between firstdegree relatives, second-degree relatives, and cousins.…”