Variation in genes relevant to aromatic hydrocarbon metabolism and the risk of adult brain tumors

Both genetic and environmental factors are likely to be important causes of primary brain tumors. The few clues about brain tumor etiology indicate that certain occupations involving exposure to polycyclic aromatic hydrocarbons (PAHs)2 or other aromatic hydrocarbons may be associated with increased risk (Inskip, P.D., et al., 1995), most notably work in the petroleum industry (Carozza et al., 2000; Demers et al., 1991; Preston-Martin, 1989; Thomas et al., 1986, 1987); however, multiple exposures in implicated occupations limit possible conclusions about aromatic hydrocarbons. Smoking, a major source of aromatic hydrocarbon exposure, has been associated with brain tumor incidence in several studies (Burch et al., 1987; Lee et al., 1997), but not consistently so (Inskip, P.D., et al., 1995), and sometimes only among certain subgroups (Efird et al., 2004; Phillips et al., 2005). It is possible that underlying variability in genes responsible for biotransformation and metabolism of aromatic hydrocarbons could hinder the consistency of studies of chemical exposures. For this reason, it may be illuminating to study the association of variants in genes involved in aromatic hydrocarbon metabolism with the risk of brain tumors. The conversion of PAHs to DNA-reactive products depends on a complex series of biotransformations. In the case of benzo[a]pyrene, transformation events include oxidation by cytochrome P-450 enzymes (such as CYP1A1) to create the active benzo[a]pyrene epoxide (Pelkonen and Nebert, 1982; Shimada et al., 1996), hydration by microsomal epoxide hydrolase (EPHX1) to the less toxic benzo[a]pyrene diol, oxidation by P-450 enzymes (such as CYP1B1) to the highly carcinogenic benzo[a]pyrene diol epoxide, detoxification of benzo[a]-pyrene and benzo[a]pyrene diol epoxide by glutathione S-transferases (such as GSTM1, GSTT1, and possibly GSTM3) by addition of reduced glutathione to electrophilic compounds (Omiecinski et al., 2000; Strange et al., 2001), and reduction of oxidative potential of quinones derived from benzo[a]pyrene diol by NAD(P)H:quinone oxidoreductase 1 (NQO1) (Palackal et al., 2002; Pastorelli et al., 1998; Ross et al., 2000). There is evidence from animal experiments that NAD(P)H protects from PAH-induced carcinogenicity; this protection is thought to operate through decreases in quinone-induced DNA adduct formation and DNA mutagenicity, including that induced by benzo[a]pyrene quinine (Joseph and Jaiswal, 1998; Long et al., 2001). In a previous report, we presented case-control study results for some genes known to be involved in metabolism of PAHs or other potential carcinogens, namely, CYP2E1, GSTM1, and GSTT1 (De Roos et al., 2003). For the current investigation, we selected several additional candidate genes related to PAHs or other aromatic hydrocarbons; all of the selected metabolic genes exhibit sequence variation that may relate to function. Substitution of valine with isoleucine in exon 7 of CYP1A1 results in a variant (I462V) with increased arylhydrocarbon hydroxylase activity (Cosma et al., 1993; Crofts et al., 1994; Kiyohara et al., 1996, 1998; Taioli et al., 1995). The functional significance of a CYP1B1 variant, V432L, is not well known; however, some studies suggest that the valine product results in higher catalytic activity toward some PAH dihydrodiols relative to leucine (Shimada et al., 1999), possibly leading to increased levels of reactive intermediates. The GSTM3 gene has a three-base-pair deletion in intron 6, and the two alleles are referred to as GSTM3*A and GSTM3*B (Inskip, A., et al., 1995; Strange et al., 2001). This deletion creates a recognition motif (-aagata-) for the YY1 transcription factor which could potentially affect detoxification activity by GSTM3*B (Strange et al., 2001). The EPHX1 variant Y113H has demonstrated increased activity in vitro but not in vivo (Hassett et al., 1994; Omiecinski et al., 2000). In vitro, EPHX1 activity is increased (about 40%) when associated with the histidine product, probably because of altered protein stability (Hassett et al., 1994). The NQO1 P187S variant resulting from C-to-T substitution leads to reduced enzyme function (Moran et al., 1999; Traver et al., 1997) and thus, presumably, less protection against oxidative damage. We examined the effects of these metabolic gene variants in a parallel comparison of three major categories of malignant and benign brain tumors, namely the gliomas, meningiomas, and acoustic neuromas. Although we selected genes according to their possible relevance to metabolism of PAHs and other aromatic hydrocarbons, the substrate specificity is quite broad, and it is unclear to what extent the selected genes reflect a coherent pathway. Nevertheless, this exploratory approach was considered appropriate, given the dearth of knowledge about causes of brain tumors.