Risk of Bladder Cancer Associated with Family History of Cancer: Do Low-Penetrance Polymorphisms Account for the Increase in Risk? Cristiane Murta-Nascimento, 1,2 Debra T. Silverman, 4 Manolis Kogevinas, 1,2 MontserratGarcı´a-Closas, 4 Nathaniel Rothman, 4 Adonina Tardo ´n, 5 ReinaGarcı´a-Closas, 6 Consol Serra, 3,7 Alfredo Carrato, 8 Cristina Villanueva, 1,2 Mustafa Dosemeci, 4 Francisco X. Real, 1,3 and Nu ´ria Malats 1,2 1 Institut Municipal d’Investigacio ´ Me `dica; 2 Centre de Recerca en Epidemiologia Ambiental; 3 Universitat Pompeu Fabra, Barcelona, Spain; 4 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland; 5 Universidad de Oviedo, Oviedo, Spain; 6 Unidad de Investigacio ´n, Hospital Universitario de Canarias, La Laguna, Spain; 7 Consorci Hospitalari Parc Taulı ´, Sabadell, Spain; and 8 Hospital General de Elche, Elche, Spain Abstract The relationship between family history of cancer in first- degree 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 indi- viduals 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) Introduction The incidence of bladder cancer in Spain is the highest in the western world and the second at the worldwide level after Egypt (1). In Egypt, most of the bladder cancers are of squamous histology, whereas in Spain they are urothelial cell carcinomas. It is estimated that f12,215 new cases of bladder cancer occurred in Spain in 2002 (1). This makes bladder cancer the fourth most common cancer in men (33 new cases per 100,000 persons per year) and the 15th in women (3.5 per 100,000 persons per year). Tobacco smoking and occupational exposure to aromatic amines are the most important risk factors for this disease (2, 3) but other lifestyle/environmental as well as hereditary factors have also attracted much interest. Among the hereditary factors involved in bladder cancer carcinogenesis, the role of variation in the genes coding for xenobiotic biotransforming enzymes such as N-acetyltransfer- ase 2 (NAT2 ) and glutathione S -transferase M1 (GSTM1 ) has been most extensively studied (4-6). Recent meta-analyses of 31 case-control studies assessing the risk of bladder cancer conferred by NAT2 -slow acetylating genetic variants and of 28 case-control studies assessing the risk of bladder cancer conferred by GSTM1 -null variants estimated odds ratios (OR) of 1.4 [95% confidence interval (95% CI), 1.2-1.6] and 1.5 (95% CI, 1.3-1.6), respectively (6). Indeed, this is the tumor for which strongest evidence is available on a role of low- penetrance genetic variants in both increasing cancer risk and in gene-environment interactions (6). By contrast, research on familial aggregation of bladder cancer has been less extensive and the results of case-control studies remain controversial (7-11). Family history of other types of cancer such as lymphocytic leukemia, cervical, pancreas, kidney, thyroid, and nervous system cancer has also been associated with an increased risk of bladder cancer (12-16). Several case reports of families with multiple affected relatives have been published (17-22) but high-penetrance genes have not been identified (23). Therefore, it is possible that, as in breast cancer, familial aggregation of cancer may be due to additive effects of several common, low-penetrance gene variants that cosegregate within families (24). In this report, we assessed the relationship between bladder cancer risk and the reported history of any other type of cancer, including bladder cancer, among first-degree relatives using data from the Spanish Bladder Cancer Study. We have also investigated whether variants of NAT2 and GSTM1 1595 Cancer Epidemiol Biomarkers Prev 2007;16(8). August 2007 Received 9/1/06; revised 5/21/07; accepted 5/25/07. Grant support: Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA, and Fondo de Investigacio ´n Sanitaria, Spain, grants 96/1998-01, 00/0745, G03/174, G03/160, C03/09, C03/10, and PI051436. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Nu ´ria Malats, Centre de Recerca en Epidemiologia Ambiental (CREAL), Institut Municipal d’Investigacio ´ Me `dica (IMIM), Carrer del Dr. Aiguader 88, E-08003, Barcelona, Spain. Phone: 34-933-160-671; Fax: 34-933-160-575. E-mail: nuria@imim.es Copyright D 2007 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-06-0743