Risk of Bladder Cancer Associated with Family History of Cancer: Do Low-Penetrance Polymorphisms Account for the Increase in Risk?

Abstract

The relationship between family history of cancer in firstdegree relatives and risk of bladder cancer was examined in the Spanish Bladder Cancer Study. Information on family history of cancer was obtained for 1,158 newly diagnosed bladder cancer cases and 1,244 controls included in 18 hospitals between 1998 and 2001. A total of 464 (40.1%) cases and 436 (35.1%) controls reported a family history of cancer in z1 relative [odds ratio (OR), 1.32; 95% confidence interval (95% CI), 1.11-1.59]; the OR was 1.23 (95% CI, 1.01-1.50) among those with only one relative affected and 1.67 (95% CI, 1.23-2.29) among those with z2 affected relatives (P trend = 0.0004). A greater risk of bladder cancer was observed among those diagnosed at age V45 years (OR, 2.67; 95% CI, 1.10-6.50) compared with those diagnosed over age 45 years (OR, 1.27; 95% CI, 1.06-1.52). The OR of bladder cancer among subjects reporting a family history of cancer of the bladder was 2.34 (95% CI, 0.95-5.77). Statistically significant associations emerged between bladder cancer risk and family history of cancer of the esophagus, lung, prostate, and brain. The OR of bladder cancer for those reporting family history of bladder cancer was 4.76 (95% CI, 1.25-18.09) among NAT2-slow acetylators and 1.17 (95% CI, 0.17-7.86) among NAT2-rapid/ intermediate acetylators (P interaction = 0.609). Among individuals with GSTM1 null and present genotypes, the corresponding ORs were 2.91 (95% CI, 0.44-19.09) and 4.21 (95% CI, 1.26-14.14), respectively (P interaction = 0.712). Limitations of our study are small sample size in subgroup analyses, reliability of family history data, and possible residual confounding by shared environmental exposures. Overall, our findings support the hypothesis that genetic factors play a role in bladder cancer etiology. Whether these correspond to low-penetrance cancer-predisposing polymorphisms acting together and/or interacting with environmental factors warrants further research. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1595 -600)

The origins of bladder cancer

“…39 Such data support the concept of low-penetrance cancer-predisposing polymorphisms acting together and/or interacting with environmental factors, to increase the familial risk of bladder cancer. 40 However, the familial risk of bladder cancer is not well understood and, to date, little attention has been paid to the joint effect of smoking and family history in modifying the risk of bladder cancer, in part because of the limitations of case control studies. This limitation was overcome in a family-based population analysis of incident bladder cancer, in which probands who had smoked and who also had a positive family history were at 5.31-fold increased risk of bladder cancer.…”

Familial and genetic risk of transitional cell carcinoma of the urinary tract

“…Table 4 summarizes pertinent details of 9 case-control and 4 cohort studies in which family history of TCCUT was quantitatively evaluated as a bladder cancer risk factor. [12][13][14][15][16][17][18][19][20][21][22][23][24] These studies varied widely in sample size, quality of design and analysis, inclusion/exclusion of upper urinary tract sites, and the extent to which reported cancers were objectively documented, but are surprisingly similar in their estimated risk ratios. These range from 1.2 to 6.1 among male and female cases combined, with most of the results clustering between 1.4 and 1.9.…”

“…[2,7] Common variants in low-penetrance genes involved in the metabolism of environmental toxins have been shown to modify individual susceptibility to bladder carcinogens. [2] Furthermore, a genetic predisposition to bladder cancer is suggested by the occurrence of TCCUT in several Mendelian disorders [8][9][10][11], epidemiologic studies showing that a positive TCCUT family history increases bladder cancer risk [12][13][14][15][16][17][18][19][20][21][22][23][24], and a limited number of case reports describing multiple-case TCCUT families. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] Therefore, both genetic and environmental factors play a role in the development of bladder and related urinary tract cancers.…”

Hereditary bladder cancer

“…Another large caseÁcontrol study from Spain among 1158 bladder cancer cases and 1244 controls found an increased risk of bladder cancer by a factor of 2.34 (95% CI 0.95Á5.77) for those reporting a positive family history of bladder cancer [12] Goldgar et al [13] estimated O/E ratios in the Utah Population Database by identifying all cases of cancer in first degree relatives of patients. The first degree relatives of bladder cancer probands were found to have an increased risk of bladder cancer of 1.5 (95% CI 1.0Á2.2) (not adjusted for smoking).…”