• Division of Cancer Epidemiology and Genetics (JDF, SK, JSC, MGC, MCF, DB, PS, LEM, LPO, ARB, AP, JFFJr, SJC, NC, NR, DTS), Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research (KY, JYC, SMH), and Cancer and Inflammation Program (MLN), National Cancer Institute, Bethesda, MD; Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh UK (JDF); CIBERESP, CIBER Epidemiologia y Salud Publica, Madrid, Spain (MK, AT, JL); Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain (MK); Municipal Institute of Medical Research (IMIM-Hospital del Mar), Barcelona, Spain (MK); Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK (MGC); Spanish National Cancer Research Centre (CNIO), Madrid, Spain (FXR, NM); Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain (FXR, CS); Maine Cancer Registry, Augusta, ME (MS); Vermont Cancer Registry, Burlington, VT (AJ); Geisel School of Medicine at Dartmouth, Hanover, NH (MRK, AS); New Hampshire Department of Health and Human Services, Concord, NH (KRA); Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc. (formerly SAIC-Frederick, Inc.), Frederick National Laboratory for Cancer Research, Frederick, MD (PL); Molecular Epidemiology Group, Instituto Universitario de Oncologia, Universidad de Oviedo, Oviedo, Asturias, Spain (AT); Hospital Ramón y Cajal, Elche, Madrid, Spain (AC); Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain (RGC).

Few studies have demonstrated gene/environment interactions in cancer research. Using data on high-risk occupations for 2258 case patients and 2410 control patients from two bladder cancer studies, we observed that three of 16 known or candidate bladder cancer susceptibility variants displayed statistically significant and consistent evidence of additive interactions; specifically, the GSTM1 deletion polymorphism (P interaction ≤ .001), rs11892031 (UGT1A, P interaction = .01), and rs798766 (TMEM129-TACC3-FGFR3, P interaction = .03). There was limited evidence for multiplicative interactions. When we examined detailed data on a prevalent occupational exposure associated with increased bladder cancer risk, straight metalworking fluids, we also observed statistically significant additive interaction for rs798766 (TMEM129-TACC3-FGFR3, P interaction = .02), with the interaction more apparent in patients with tumors positive for FGFR3 expression. All statistical tests were two-sided. The interaction we observed for rs798766 (TMEM129-TACC3-FGFR3) with specific exposure to straight metalworking fluids illustrates the value of integrating germline genetic variation, environmental exposures, and tumor marker data to provide insight into the mechanisms of bladder carcinogenesis.