Genetic Alterations in Cancer Knowledge System: Analysis of Gene Mutations in Mouse and Human Liver and Lung Tumors

TOXICOLOGICAL SCIENCES 90(2), 400–418 (2006) doi:10.1093/toxsci/kfj101 Advance Access publication January 12, 2006 Genetic Alterations in Cancer Know...
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TOXICOLOGICAL SCIENCES 90(2), 400–418 (2006) doi:10.1093/toxsci/kfj101 Advance Access publication January 12, 2006

Genetic Alterations in Cancer Knowledge System: Analysis of Gene Mutations in Mouse and Human Liver and Lung Tumors Marcus A. Jackson,* Isabel Lea,* Asif Rashid,† Shyamal D. Peddada,‡ and June K. Dunnick‡,1 *Integrated Laboratory Systems, Inc., Research Triangle Park, North Carolina 27709; †Alpha-Gamma Technologies Inc., Raleigh, North Carolina 27609; and ‡National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 Received September 9, 2005; accepted December 9, 2005

Mutational incidence and spectra for genes examined in both human and mouse lung and liver tumors were analyzed using the National Institute of Environmental Health Sciences (NIEHS) Genetic Alterations in Cancer (GAC) knowledge system. GAC is a publicly available, web-based system for evaluating data obtained from peer-reviewed studies of genetic changes in tumors associated with exposure to chemical, physical, or biological agents, as well as spontaneous tumors. In mice, mutations in Kras2 and Hras-1 were the most common events reported for lung and liver tumors, respectively, whether chemically induced or spontaneous. There was a significant difference in Kras2 mutation incidence for spontaneous versus induced mouse lung tumors and in Hras-1 mutation incidence and spectrum for spontaneous versus induced mouse liver tumors. The major gene changes reported for human lung and liver tumors were in KRAS2 (lung only) and TP53. The KRAS2 mutation incidence was similar for spontaneous and asbestosinduced human lung tumors, while the TP53 mutation incidence differed significantly. Aflatoxin B1, hepatitis B virus, hepatitis C virus, and vinyl chloride all caused TP53 mutations in human liver tumors, but the mutation spectrum for each agent differed. The incidence of KRAS2 mutations in human compared to mouse lung tumors differed significantly, as did the incidence of Hras and p53 gene mutations in human compared to mouse liver tumors. Differences observed in the mutation spectra for agent-induced compared to spontaneous tumors and similarities in spectra for structurally similar agents support the concept that mutation spectra can serve as a ‘‘fingerprint’’ of exposure based on chemical structure. Key Words: genetic alteration; mutation; lung tumor; liver tumor; environmental exposure; database.

Cancer is a leading cause of death in the United States (Jemal et al., 2005), yet it remains a very difficult and complicated disease to understand. It is a complex process that clearly involves multiple genetic changes (Balmain 2002; Hermeking 2003), and a more complete understanding of the process will help in the implementation of cancer prevention strategies. 1 To whom correspondence should be addressed at National Institute of Environmental Health Sciences, MD EC-35, P.O. BOX 12233, Research Triangle Park, NC 27709. Fax: (919) 541-4255. E-mail: [email protected].

Information from the National Institutes of Health (NIH) on the human genome has greatly enhanced our understanding of cancer genes and their contribution, and future cancer-prevention efforts will undoubtedly rely on the use of this type of information. However, there are other critical factors to be considered, including epigenetic and environmental factors. The need still exists for better understanding the relationship(s) among environmental, genetic, and epigenetic factors regarding their individual and collective contribution to human cancer. Numerous studies have reported on individual proclivity to certain types of cancers that are attributable to inherited susceptibility genes or single nucleotide polymorphisms (SNPs) (Blankenburg et al., 2005; Demokan et al., 2005; Lee et al., 2005). These types of genes have been associated with breast cancer (BRCA1 and BRCA2), colorectal cancer (APC), and prostate cancer (ELAC2), but it is becoming more evident that environmental factors also play an important role in cancer development (Czene et al., 2002; Lichtenstein et al., 2000). As our knowledge of the genome grows, so does the opportunity for better understanding the relationships between these environmental and genetic factors. While many resources are available for identifying critical target genes or gene loci involved in cancer, there is a need to develop additional resources that expand our understanding of the relationships between genetic and environmental factors in tumor development (Birney et al., 2002). Databases such as the International Agency for Research on Cancer (IARC) TP53 Mutation Database (Olivier et al., 2002) provide a wealth of information on mutations in a single gene; however, to our knowledge no single database containing results from studies of multiple genes has been assembled. The NIEHS has recently developed the Genetic Alterations in Cancer (GAC) knowledge system to help meet this need. GAC is a web-based system for collecting, recombining, and summarizing gene mutation data that are extracted from studies published in the open literature (http://dir-apps.niehs.nih.gov/gac/). Results from human and rodent studies are included and are organized by species, strain, target organ, tumor type and origin, and agent. Data mining features used to query the database combine and summarize data from all studies that match the query criteria. The results

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GENETIC ALTERATIONS IN LIVER AND LUNG TUMORS

are presented in profile graphs or data tables that are displayed in one of four individual chart areas to facilitate comparative analysis. Although loss of heterozygosity (Pan et al., 2005; Tseng et al., 2005) and epigenetic events (reviewed by Jones, 2005) are also important factors in cancer development, the GAC system focuses primarily on gene mutations. An introduction to the GAC knowledge system is presented here along with an analysis of the mutation incidence (percentage of tumors with a mutation) and spectra (pie charts showing the percentage of each type of mutation [e.g., AT > CG, GC > TA, or deletion] based on data from all studies) for genes that have been studied in tumors associated with environmental carcinogens compared to those that occur sporadically (spontaneous). Point mutation data for multiple genes studied in lung and liver tumors from humans and mice were retrieved by the GAC program. These data were used to demonstrate chemical-, species-, and organ-specific patterns of mutations and assess possible tumor etiology. Strain differences in gene mutations have been documented for the ras genes in both chemically induced and spontaneously occurring tumors (Maronpot et al., 1995). However, the results presented here are from combined studies using various mouse strains and portray genetic variation in the species (Festing, 1995) that more closely mimics genetic variation in human populations. The analysis shows that in mice Kras2 had the highest incidence of mutation in both spontaneous and induced lung tumors, whereas in liver Hras-1 had the highest incidence. The spectrum of mutations in genes from mouse lung and liver tumors were exposure specific as were the mutation spectra for human liver tumors associated with exposure to aflatoxin B1 (AFB1), hepatitis B or C virus (HBVor HCV), or vinyl chloride (VCl). Each produced a unique mutation spectrum. Comparative analysis of the mutation spectra based on the molecular structure of the test chemical showed that the overall pattern of mutations for structurally related chemicals were remarkably alike. This information can be used to estimate the mutagenic and carcinogenic potential of structurally similar agents which have not been well studied. MATERIALS AND METHODS Data selection and entry. Comprehensive literature search strategies were used to identify studies of gene alterations in tumors associated with exposure to specific environmental agents. The search strategies were applied to the peerreviewed literature for selecting journal articles that met three critical criteria: (1) a description of the tumor(s) and indication of which ones were associated with exposure to a specific agent (e.g., occupational exposure or general population from epidemiologic or case series studies) and which were spontaneous; (2) a molecular analysis of the tumor sample for genetic alterations; and (3) the identification of the affected gene(s) and description of the gene change(s). Studies were not included when a sufficient description of the study design, including tumor topography and morphology, methods used to analyze gene changes, and appropriate control information were not given; original data were not reported (e.g., reviews); the specific base mutation was not described (e.g., A > T); or the data were from in vitro studies.

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Lung and liver tumors. Data from studies of gene mutations in lung tumors from individuals evaluated for asbestos exposure and in liver tumors of individuals exposed to AFB1, HBV, and/or HCV were extracted and entered into the system. Gene mutation data from studies of chemically induced and spontaneous (control) lung and liver tumors in mice were also included. Since data are continually added to the database and new data made available to the user each quarter, the number of studies displayed in the GAC database, particularly for spontaneous tumors, will be greater than the numbers included in the analysis presented here. The data were organized into two Agent Groups, ‘‘Induced’’ and ‘‘Spontaneous.’’ Tumors from unexposed human subjects (e.g., result from questionnaire, personal monitoring device, control subjects) or those with no reported exposure, along with tumors from control animals, were assigned to the ‘‘Spontaneous’’ group. Tumors that were associated with exposure of individuals to a specified agent (e.g., AFB1 from living in a high exposure area; biomarker of exposure such as protein adducts) and tumors induced in experimental animals by treatment with a specific test agent were assigned to the ‘‘Induced’’ group. The primary data fields used for data entry and summaries include study information: species and strain; tumor information: topography, morphology, tumor origin (e.g., primary or recurrent), number of tumors, and alteration category (gene or chromosome); subject group information: exposure category (e.g., acute or chronic), route, dose, frequency, exposure time, sampling time, geographic region, and ethnicity; subject tumor information: individual subject identification, genetic disorder (if applicable), gender, age, and confounding factor (e.g., scar tissue); and alteration data: gene symbol, exons evaluated, alteration type (e.g., point mutation), analytical technique, affected codon, type of base change (e.g., C > T), alteration description (e.g., GC > AT), wild-type codon sequence and amino acid, and altered codon sequence and predicted amino acid. Note fields for clarifying discrepancies between the published data and that shown in GAC (e.g., amino acid predicted in a study was wrong) or to provide additional study information that could affect data comparisons are also included. Statistical analysis. Data for human and mouse lung and liver tumors were retrieved from the database using the data mining features and were organized by species, tumor site, and agent group (spontaneous or induced). Data from detailed data lists showing the results for each tumor sample from all studies retrieved were generated by the GAC program, captured, and prepared for broad-based statistical analysis. This included data from 46 studies of induced and spontaneous mouse lung tumors and 38 studies of mouse liver tumors. Data from 53 studies of human lung and 106 studies of liver tumors associated with exposure to specific agents or reported to be sporadic were also prepared for statistical analysis. The mutation incidence was compared for pairs of data groups (e.g., human lung and mouse lung, mouse liver induced and spontaneous, or mouse Kras2 and Hras1) using a standard two-sample Z-statistic for proportions. However, since sample proportions were derived from multiple studies, and variables between studies (e.g., strain, dose, and treatment time) were not specifically factored in, extra variation between studies was taken into account by using a nonparametric estimator for extra binomial variability (McCullagh and Nelder, 1997). The p values for the tests were derived using a nonparametric bootstrap methodology (Efron and Ribshirani, 1993). Mutation spectra for concordant genes in the different data groups were also statistically analyzed. Mutations for which a description was not given (NG) in the study or that represented GC (codon 61); 11% GC > TA (codon 12). Further analysis of the mouse Kras2 data showed that, although the mutation incidence in spontaneous compared to

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FIG. 1. Gene mutation profiles and summary tables for (A) mouse and (B) human lung tumors.

all induced lung tumors was not significantly different ( p ¼ 0.1233), the mutation spectra were ( p ¼ 0.0008). Data from studies by the NIEHS of lung tumors induced in mice by exposure to urethan (ethyl carbamate: EC) or 4-(N-nitrosomethylamino)1-(3-pyridyl)-1-butanone (NNK) are summarized in Table 2 along with the results from 16 studies of spontaneous lung tumors. The number of studies, number of tumors evaluated, and number of tumors reported to have Kras2 mutations are listed. The mutation incidence for each group is comparable, ranging from 60 to 81%; however, the mutation spectra shown in Figure 2B for these three agents are uniquely different. The majority of the mutations (73–98%) were distributed between AT > GC or GC > AT transitions or AT > TA transversions in each group, but the distribution of the mutation types was uniquely different. The percentage of AT > GC, GC > AT, and AT > TA mutations was 24, 29, and 20%, respectively, for spontaneous tumors; 31, 3, and 64%, respectively, for EC-induced tumors; and 1, 96, and GC and GC > AT transitions and AT > TA transversions (31, 3, and 64%, respectively), compared to that for VC-induced tumors (42, 13, and 33%, respectively). Due to the limited amount of data available for VC a statistical comparison was not possible.

Mouse lung tumor Kras2 mutation spectra by chemical structure (Fig. 3). The Kras2 mutation spectra for the other mouse lung carcinogens are given in Figures 3C–3L and are grouped by chemical structure. Spectra for three nonaromatic amines, diethylnitrosamine (DEN; Fig. 3C), ethylnitrosourea (ENU; Fig. 3D), and N-nitrosodimethylamine (DMN; Fig. 3E) showed that ~99% of the mutations induced by each agent were AT > GC or GC > AT transitions. The mutation pattern induced the two alkylating agents DEN and ENU are very similar (71% and 64% AT > GC and 18% and 27% GC > AT, respectively) but quite different from the spectrum induced by the nonalkylating agent DMN (5% AT > GC and 94% GC > AT) and from the spectra for the unsaturated nonaromatic amines EC and VC (discussed above). The activity of DMN is in fact comparable to that of NNK (Fig. 3F; 1% AT > GC and 96%

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FIG. 3. Kras2 mutation spectra from mouse lung tumors.

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FIG. 4. Gene mutation profiles and summary tables for (A) mouse and (B) human liver tumors.

GC > AT), a heterocyclic aromatic nitrosamine. Both of these chemicals have a methyl group attached to the N-nitroso moiety. Kras2 mutations induced by the nonnitrosated heterocyclic aromatic amines, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 7H-dibenzo[c,g]carbazole (DBC) are also similar (80% and 92% AT > TA transversions, respectively), but are uniquely different from NNK (Fig. 3F) as well as the aromatic azo-dyes 4-aminoazobenzene and benzidine, which induced 95% and 85% GC > TA transversions, respectively (data not shown). Two of three polycyclic aromatic hydrocarbons (PAH) with a cyclopentane ring, cyclopenta[cd]pyrene (Fig. 3G) and benz[j]aceanthrylene (Fig. 3H), have no bay region in their structure and induced both GC > TA and CG transversions (40% and 50% compared to 35% and 65%, respectively), while benzo[b]fluoranthene, which has a bay region that can form an epoxide, induced 92% GC > TA transversions (Fig. 3I). This activity was comparable to that of the PAH benzo[a]pyrene (B[a]P) (Fig. 3J) and 5-methylchrysene (Fig. 3K) that induced 81% and 73% GC > TA transversions, respectively. The

mutation spectrum for 1-nitropyrene (1-NP; Fig. 3L), the only nitro-PAH evaluated for Kras2 mutations, was similar to that seen for the nitrosamines DEN and ENU. It induced 83% AT > GC and 17% GC > AT transitions. Like 6-nitrochrysene (6-NC), 1-NP is primarily metabolized via nitroreductases to the aromatic amine 1-aminopyrene, which forms an N-(deoxyguanosin-8-yl)-1-aminopyrene adduct (Bai et al., 1998). Two other DNA adducts may also be formed from Nhydroxy-1-aminopyrene; they are 6-(deoxyguanosin-N2-yl)-1aminopyrene and 8-(deoxyguanosin-N2-yl)-1-aminopyrene (Herreno-Saenz et al., 1995). The reduction of 1-NP to an aromatic amine is most likely the reason for the similarity in the mutation spectra for 1-NP, DEN, and ENU. Genetic Changes in Liver Tumors An overview of the incidence of point mutations in different genes from liver tumors (spontaneous plus induced) of mice (38 studies total) and humans (106 studies total) is shown in the mutation profiles and corresponding data tables in Figures 4A

GENETIC ALTERATIONS IN LIVER AND LUNG TUMORS

and 4B. As with the profiles for the lung tumors, species differences and similarities are readily apparent, especially for the incidence of Hras, Kras, and p53 mutations. The incidence of Apc, Kras, and Nras gene mutations was comparable in both mouse and human liver tumors. The incidence of b-catenin mutations appeared to be higher in mouse (31%) than in human (17%) tumors; however the mouse data represent six studies (Anna et al., 2000; Aydinlik et al., 2001; Gotoh et al., 2003; Hayashi et al., 2003; Huang et al., 2003; Ogawa et al., 1999) compared to 17 human studies. Due to the limited amount of data from the mouse studies, statistical analysis was not possible. The median mutation incidence for the mouse compared to human data was 27% and 19%, respectively, indicating that a statistically significant difference is unlikely. The incidence of Hras and p53 gene mutations appeared to be significantly different in the liver tumor samples from humans compared to mice for this data set. Hras-1 mutations were induced in 31% (812/2605 tumors) of the mouse tumors evaluated in 40 studies but not in any of the 111 human tumor samples from seven studies. Conversely, the incidence of human liver tumors with TP53 mutations was 26% (559/2153 tumors) according to results from 64 studies compared to 0% in 250 mouse liver tumors (of which 235 were agent induced) from five studies. Statistical analyses were done on the TP53 mutation incidence and spectrum for human spontaneous compared to induced liver tumors and on the Hras-1 mutation incidence and spectrum for mouse spontaneous compared to induced liver tumors to determine if the frequency and types of mutations seen in each group for a given species were similar (see Table 1). Tumors considered to be induced in humans included those from individuals reported to live in areas of high AFB1 exposure and/or to have HBV or HCV. Results from 19 tumors in three studies of workers occupationally exposed to VCl are also in this group (Hollstein et al., 1994; Weihrauch et al., 2000, 2002). The difference between the TP53 mutation incidence in human spontaneous liver tumors (118/612 ¼ 19%; 34 studies) compared to induced tumors (441/1541 ¼ 29%; 57 studies) was marginal ( p ¼ 0.0485). Perhaps the reason for this lies in the heterogeneous nature of the human spontaneous tumor group; a variety of environmental exposures are probable in these patients, but are not reported in the literature. The overall TP53 mutation spectra for the human liver tumor data are shown in Figure 5A. The TP53 mutation spectrum for spontaneous tumors was significantly different from the spectrum for the induced tumors ( p < 0.0001). A major factor that contributed to this difference is the extensive amount of data reported in numerous studies that specifically analyzed codon 249ser mutations in hepatocellular carcinomas (HCC). This is the most frequent mutation seen in HCC from populations exposed to relatively high levels of AFB1 in the diet. The GC > TA missense mutation in codon 249 causes an AGGarg / AGTser sequence change. Over 50% of the mutations shown in

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the TP53 mutation spectra in Figure 5A for induced tumors are GC > TA transversions that have been reported in studies from moderate to high AFB1 exposure areas. The Hras-1 mutation incidence calculated from data in 21 studies of spontaneous mouse liver tumors (290/670 ¼ 43%) was also significantly different from that calculated for chemically induced tumors (522/1935 ¼ 27%) reported in 32 studies ( p ¼ 0.021). The mutation spectra for several classes of the chemicals represented in the induced group and the results from the analysis of these spectra are described below. Data presented in Figure 5B for Hras-1 mutations in spontaneous compared to chemically induced mouse liver tumors showed a significant difference ( p < 0.0001; Table 1) between the two mutation spectra. Approximately 60% of the induced tumor data are for three agents, DEN, VC, and methylene chloride (MeCl) from 18 studies. The mutation spectrum for each of these agents was also unique. The percentage of AT > GC and GC > TA transitions and AT > TA transversions for DEN-induced tumors from 14 studies (see Fig. 7D for citations) was 38, 36, and 24%, respectively; for VC-induced tumors (Stanley et al., 1992; Watson et al., 1995; Wiseman et al., 1986) it was 28, 12, and 60%, respectively; and for MeCl-induced tumors (Hegi et al., 1993) it was 42, 42, and 16%, respectively. Finally, statistical analyses were done on selected gene mutation spectra for lung compared to liver tumors from the same species. The TP53 mutation spectra for human spontaneous lung compared to liver tumors are shown in Figure 6. The spectra were significantly different ( p ¼ 0.0094), as was the incidence of TP53 mutations in lung (42%) compared to liver (19%; p ¼ 0.0076). The incidence of mutations in Kras2 also differed significantly in mouse lung compared to liver tumors for both spontaneous ( p ¼ 0.0065) and induced ( p < 0.0001) tumors, as did their mutation spectra ( p < 0.0001). Mouse liver tumor Hras-1 mutation spectra by chemical structure (Fig. 7). The mutation spectra for Hras-1 showed that the nonaromatic amines induced primarily AT > TA or GC transversions and transitions in contrast to the aromatic amines that predominantly induced GC > TA transversions (60 to 100%). The mutation spectra for EC and its metabolite VC, both unsaturated nonaromatic amines, are almost identical (~60% AT > TA transversions and 28% AT > GC transitions; Figs. 7A and 7B), yet they are noticeably different from the spectra for the nonaromatic nitrosamines, DMN and DEN (Figs. 7C and 7D). These nitrosamines had a higher incidence of AT > GC transitions (55 and 38%, respectively) and a lower incidence of AT > TA transversions (14 and 24%, respectively). The incidence of GC > TA transversions was 32 and 36%, giving an overall transversion incidence of 46 to 60%. The two amines with nonfused benzene rings, benzidine and 4-aminobiphenyl, had a lower incidence of GC > TA transversions (85% and 60%, respectively; Figs.7E and 7F) compared to the two aromatic amines, 2-acetylaminofluorene

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FIG. 5. Mutation spectra for spontaneous and agent-induced liver tumors for (A) the human TP53 gene, and (B) the mouse Hras-1 gene. (A) Human liver TP53 references—Spontaneous (underlined papers have data for spontaneous and induced tumors): An et al., 2001; Boix-Ferrero et al., 1999; Bourdon et al., 1995; Challen et al., 1992; Deng et al., 1997; Hayashi et al., 1993; Hollstein et al., 1993; Hsieh and Atkinson, 1995; Jin et al., 2002; Kar et al., 1993; Karachristos et al., 1999; Kazachkov et al., 1996; Kennedy et al., 1994; Kress et al., 1992; Kubicka et al., 1995; Lai et al., 1993; Laurent-Puig et al., 2001; Murakami et al., 1991; Nishida et al., 1993; Oda et al., 1992b; Park et al., 1996; Pogribny and James, 2002; Sahoo et al., 1993; Shi et al., 1995; Shieh et al., 1993; Shimizu et al., 1999; Soini et al., 1996; Tanaka et al., 1993; Tannapfel et al., 2001; Vautier et al., 1999; Vesey et al., 1994; Volkmann et al., 2001; Wong et al., 2000; Zhu et al., 2002. Human liver TP53 references—Induced: Bressac et al., 1991; Buetow et al., 1992; Chao et al., 1999; De Benedetti et al., 1995; Diamantis et al., 1994; Fujimoto et al., 1994; Goldblum et al., 1993; Greenblatt et al., 1997; Hollstein et al., 1994; Hoque et al., 1999; Hosono et al., 1993; Hsia et al., 2000; Hsu et al., 1991; Katiyar et al., 2000; Lee et al., 2002; Li et al., 1993; Lunn et al., 1997; Ng et al., 1994a,b; Nose et al., 1993; Oda et al., 1992a; Ozturk, 1991; Rashid et al., 1999; Scorsone et al., 1992; Sheu et al., 1992; Stern et al., 2001; Unsal et al., 1994; Weihrauch et al., 2000, 2002; Yang et al., 1997. (B) Mouse Liver Hras-1 references— Spontaneous (underlined papers have data for spontaneous and induced tumors): Buchmann et al., 1991; Devereux et al., 1993b; Dragani et al., 1991; Enomoto et al., 1993; Fox et al., 1990; Frey et al., 2000; Herzog et al., 1993; Hong et al., 1998; Iida et al., 2000; Johansson et al., 1997; Lord et al., 1992; Malarkey et al., 1995; Manam et al., 1995; Manjanatha et al., 1996; Mori et al., 1995; Richardson et al., 1992a; Rumsby et al., 1991; Shinder et al., 1993; Stanley et al., 1992; Von Tungeln et al., 1999; Watson et al., 1995. Mouse Liver Hras-1 references—Induced: Aydinlik et al., 2001; Bauer-Hofmann et al., 1990, 1992; Chen et al., 1993; Gotoh et al., 2003; Huang et al., 2003; Kalkuhl et al., 1996; 1998; Lee and Drinkwater, 1995; Manam et al., 1992b, 1995; Mitchell and Warshawsky, 1999; Richardson et al., 1992b; Schroeder et al., 1997; Stowers et al., 1988; Wang et al., 1993; Wiseman et al., 1986; Xia et al., 1998.

(2-AAF) and N-hydroxy-2-acetylaminofluorene (OH-2-AAF), (93% and 100%, respectively; Figs. 7G and 7H). Two PAHs, B[a]P and 7,12-dimethylbenz[a]anthracene (DMBA), primarily induced AT > TA transversions (80% and 92%; Figs. 7I and 7J), and the incidence was higher than that seen

with the nonaromatic amines. Conversely, the mutation spectra for the sole nitro-PAH, 6-NC, showed only 5% AT > TA transversions and 95% GC > TA transversions (Fig. 7K). This spectrum matched that of the two aromatic amines, 2-AAF and OH-2-AAF (93–100% GC > TA transversions). This similarity is likely due to

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FIG. 6. TP53 gene mutation spectra for human spontaneous lung and liver tumors. Human TP53 Spontaneous tumors—Lung: Hayashi et al., 1996; Kishimoto et al., 1992; Mao et al., 1994; Miller et al., 1992; Mitsudomi et al., 1993; Mor et al., 1997; Reichel et al., 1994; Sameshima et al., 1992; Sanchez-Cespedes et al., 1999; Segers et al., 1995; Takahashi et al., 1991; Taniguchi et al., 1996; Tomizawa et al., 1999; Top et al., 1995. Human TP53 Spontaneous tumors—Liver: An et al., 2001; Boix-Ferrero et al., 1999; Bourdon et al., 1995; Challen et al., 1992; Deng et al., 1997; Hayashi et al., 1993; Hollstein et al., 1993; Hsieh and Atkinson, 1995; Jin et al., 2002; Kar et al., 1993; Karachristos et al., 1999; Kazachkov et al., 1996; Kennedy et al., 1994; Kress et al., 1992; Kubicka et al., 1995; Lai et al., 1993; Laurent-Puig et al., 2001; Murakami et al., 1991; Nishida et al., 1993; Oda et al., 1992b; Park et al., 1996; Pogribny and James, 2002; Sahoo et al., 1993; Shi et al., 1995; Shieh et al., 1993; Shimizu et al., 1999; Soini et al., 1996; Tanaka et al., 1993; Tannapfel et al., 2001; Vautier et al., 1999; Vesey et al., 1994; Volkmann et al., 2001; Wong et al., 2000; Zhu et al., 2002.

6-NC being activated by nitro reduction to intermediate aromatic amines (i.e., N-hydroxy-6-aminochrysene or trans-1,2-dihydroxy1,2-dihydro-6-aminochrysene) that react with DNA much like 2-AAF and OH-2-AAF (Delclos et al., 1989).

(Phillips, 2005) due to strain and organ site differences (Festing, 1995; Festing et al., 1998).

Liver Hras-1 mutations versus lung Kras2 mutations in mouse tumors. Five chemicals had mutation spectra for both Hras-1 in liver tumors and Kras2 in lung tumors. For three of these chemicals, B[a]P, DMN, and DEN, the spectrum for each gene is visibly different (Figs. 3C, 3E, 3J, 7C, 7D, and 7I). As shown in Table 3, B[a]P induced 100% GC > TA or AT mutations in Kras2 and 90% AT > TA or GC mutations in Hras-1; DMN induced 94% GC > AT mutations in Kras2 and 69% AT > GC or TA and 32% GC > TA mutations in Hras-1; and DEN induced 71% AT > GC and 18% GC > AT mutations in Kras2 compared to 62% AT > GC or TA and 36% GC > TA mutations in Hras-1. The Hras-1 mutation spectra for the remaining two agents, EC and its metabolite VC, were essentially the same for mouse liver tumors (~60% AT > TA and 28% AT > GC mutations), but the Kras2 mutation spectra for lung tumors differed. EC induced 64% AT > TA and 31% AT > GC mutations, and VC 33% AT > TA and 42% AT > GC mutations. It is interesting to note that the Kras2 and Hras-1 mutation spectra of EC in lung and liver, respectively, are the same as that for Hras-1 in VCinduced liver tumors, suggesting that EC metabolism in the lung may produce mutagenic metabolites other than VC. Studies have shown organ susceptibilities to tumor formation which may be based on differences in metabolic capabilities (Xue and Warshawsky, 2005) and formation of DNA adducts

DISCUSSION

Results from recent studies demonstrate that environmental factors are a major contributor to human cancers and may even play a greater role than hereditary factors in the development of some types of cancers (Czene et al., 2002; Lichtenstein et al., 2000). It is well established that gene–environment interactions underlie almost all human diseases (Khoury et al., 2005). As efforts in genomic research continue toward establishing a better understanding of the role of individual genes, gene– gene interactions, and how alterations in gene sequences contribute to the disease, new approaches are also needed for expanding our understanding of controllable environmental factors that alter such critical genes so that prevention and treatment of disease can be improved. As part of this effort, we have designed a system that merges data from peer-reviewed studies of mutations in multiple genes from different types of tumors that are associated with exposure to specific agents. This system allows a retrospective analysis of various factors, including environmental exposure that can contribute to cancer development. Data can be queried by species, strain, topography, morphology, agent of interest, tumor origin, heritable factors for known disorders, or any combination of these fields. The results from the analysis of lung and liver tumor data showed that the mutation incidence and spectra for concordant

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FIG. 7. Hras-1 mutation spectra from mouse liver tumors.

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TABLE 3 Summary of ras Gene Mutation Profiles for B[a]P-, DMN-, DEN-, EC- and VC-Induced Mouse Lung and Liver Tumors Agent

CASRN

AT > TA

AT > GC

GC > AT

GC > TA

Total

Structural group

Lung B[a]P DMN DEN EC VC

50–32–8 62–75–9 55–18–5 51–79–6 15805–73–9

0 1 0 64 33

81 5 71 31 42

Kras2 mutations (percent of total mutations) 19 0 94 0 18 11 3 0 13 8

100 100 100 98a 96b

PAH Nonaromatic Nonaromatic Nonaromatic Nonaromatic

nitrosamine nitrosamine amine unsaturated amine unsaturated

Liver B[a]P DMN DEN EC VC

50–32–8 62–75–9 55–18–5 51–79–6 15805–73–9

80 14 24 67 60

10 55 38 28 28

Hras-1 mutations (percent of total mutations) 0 0 0 31 2 36 0 5 0 12

90c 100 100 100 100

PAH Nonaromatic Nonaromatic Nonaromatic Nonaromatic

nitrosamine nitrosamine amine unsaturated amine unsaturated

a

2% AT > CG or NG. 4% AT > CG. c 10% GC > CG mutations. b

sets of genes from human and mouse tumors differed significantly between agents, species, and/or topographies. The predominant mutations in mouse lung tumors were in the Kras2 gene, followed by mutations in Hras-1 and Trp53. In human lung tumors the predominant mutations occurred in the TP53 gene, followed by mutations in KRAS2 and other genes. Less than 1% (3/308 tumors) of the human lung tumors had HRAS-1 mutations. The mutational spectrum for the p53 gene was also different in mouse and human lung tumors. TP53 appears to play the most significant role in lung tumor development in humans, while Kras2, and to a lesser degree Hras-1, seem to be more important in mouse lung tumor development. This is based on the statistically significant difference seen in both the mutational incidence and spectra for these two genes that were evaluated in both species. It is of course possible that these differences reflect the disparity in the types of agent exposures in human populations compared to the experimentally controlled exposures of mice. As more data become available in the database, statistical tests that take account for many of these variables can be applied. The role of KRAS2 in human lung and liver appears to be similar based on the evidence that there is no statistically significant difference in the mutation incidence for spontaneous tumors in these two tissues. However, the exact mutations that occur in the KRAS2 gene in lung compared to liver tumors do differ significantly, indicating that the mutations may be mediated by different factors in the different tissue types. The analysis of Hras and p53 gene mutation incidence in human compared to mouse liver tumors also showed a difference between the two species. The predominant mutations in mouse liver were found in the Hras-1 gene, followed by Catnb and Kras2. In human liver tumors, mutations were found in TP53, KRAS2, and CTNNB1. The mutation incidence was similar in both species for b-catenin and the K- and Nras genes.

The Hras-1 mutation spectra for mouse liver tumors showed a significant difference between spontaneous and induced tumors. Likewise, analysis of TP53 mutations in human liver tumors showed a significant difference in the mutation spectrum for sporadic compared to induced tumors. Our analysis of mutation patterns in chemically induced mouse lung and liver tumors corroborates the large body of data from work dating back to 1958 (Benzer and Freese, 1958), where 5-bromouracil–specific mutations were shown to be induced in phage T4, and subsequent studies that reported similar observations in human cell populations (Albertini and Hayes, 1997; Cariello et al., 1990). These findings provide strong evidence that chemical exposures often induce mutations not normally found in spontaneous tumors that can be important events contributing to tumor development. Using the GAC knowledge system, we compared the mutation spectra from a wide variety of chemicals based on chemical structures. In doing so, we were able to show that specific common chemical characteristics among agents often produce remarkably similar mutation profiles. Further development of the system should allow estimates to be made regarding the carcinogenic potential of structurally similar chemicals based on mutation spectra, but this remains to be tested. A parallel mechanism of carcinogenesis introduced by Slaughter et al. (1953), some 50 years ago, suggested that when a cell which acquires a genetic alteration, such as a mutation, the change can confer a growth advantage on that cell, leading to clonal expansion and tumor development (Prevo et al., 1999; Stern et al., 2002). Elucidating which types of mutations and genes can confer a growth advantage to a cell is also an important future step toward understanding key events in the initiation of carcinogenesis. The NIEHS focus on environmental causes of cancer helps promote prevention strategies by identifying modifiable risk

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factors. Information in GAC, along with data from other studies such as gene expression and SNP analysis, provides a resource for investigation of these types of environmental and genetic factors that are involved in tumor development. The comprehensive data available in the system can be recombined to evaluate gene responses in specific types of tumors from different species exposed to a common agent, in tumors from different target sites in the same species exposed to a common agent, or in tumors from the same species exposed to different agents. This system is dynamic, with new data being added regularly; future additions to the database will include genetic alterations in preneoplastic lesions and alteration such as loss of heterozygosity in chromosomes. The GAC knowledge system is available on the NIEHS website. Nominations for additional gene analysis studies may be made to the NIEHS National Toxicology Program nomination office (http://ntp-server.niehs.nih.gov/).

Bauer-Hofmann, R., Buchmann, A., Wright, A. S., and Schwarz, M. (1990). Mutations in the Ha-ras proto-oncogene in spontaneous and chemically induced liver tumours of the CF1 mouse. Carcinogenesis 11, 1875–1877. Bauer-Hofmann, R., Klimek, F., Buchmann, A., Muller, O., Bannasch, P., and Schwarz, M. (1992). Role of mutations at codon 61 of the c-Ha-ras gene during diethylnitrosamine-induced hepatocarcinogenesis in C3H/He mice. Mol. Carcinog. 6, 60–67. Benzer, S., and Freese, E. (1958). Induction of specific mutations with 5-bromouracil. Proc. Natl. Acad. Sci. U.S.A. 44, 112–119. Birney, E., Clamp, M., and Hubbard, T. (2002). Databases and tools for browsing genomes. Annu. Rev. Genomics Hum. Genet. 3, 293–310. Blankenburg, S., Konig, I. R., Moessner, R., Laspe, P., Thoms, K. M., Krueger, U., Khan, S. G., Westphal, G., Berking, C., Volkenandt, M., et al. (2005). Assessment of 3 xeroderma pigmentosum group C gene polymorphisms and risk of cutaneous melanoma: A case-control study. Carcinogenesis 26, 1085–1090. Boix-Ferrero, J., Pellin, A., Blesa, R., Adrados, M., and Llombart-Bosch, A. (1999). Absence of p53 gene mutations in hepatocarcinomas from a Mediterranean area of Spain. A study of 129 archival tumour samples. Virchows Arch. 434, 497–501.

SUPPLEMENTARY DATA

Bourdon, J. C., D’Errico, A., Paterlini, P., Grigioni, W., May, E., and Debuire, B. (1995). p53 Protein accumulation in European hepatocellular carcinoma is not always dependent on p53 gene mutation. Gastroenterology 108, 1176–1182.

Supplementary data are available online at http://toxsci. oxfordjournals.org/.

Bressac, B., Kew, M., Wands, J., and Ozturk, M. (1991). Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350, 429–431.

ACKNOWLEDGMENTS

Brose, M. S., Volpe, P., Feldman, M., Kumar, M., Rishi, I., Gerrero, R., Einhorn, E., Herlyn, M., Minna, J., Nicholson, A., et al. (2002). BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 62, 6997–7000.

We thank Dr. R. Sills, Dr. M. Waters, and Dr. R. Maronpot for their review of the manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences Contract No. N43-ES-15477.

Buchmann, A., Bauer-Hofmann, R., Mahr, J., Drinkwater, N. R., Luz, A., and Schwarz, M. (1991). Mutational activation of the c-Ha-ras gene in liver tumors of different rodent strains: Correlation with susceptibility to hepatocarcinogenesis. Proc. Natl. Acad. Sci. U.S.A. 88, 911–915.

REFERENCES

Buetow, K. H., Sheffield, V. C., Zhu, M., Zhou, T., Shen, F. M., Hino, O., Smith, M., McMahon, B. J., Lanier, A. P., London, W. T., et al. (1992). Low frequency of p53 mutations observed in a diverse collection of primary hepatocellular carcinomas. Proc. Natl. Acad. Sci. U.S.A. 89, 9622–9626.

Albertini, R. J., and Hayes, R. B. (1997). Somatic cell mutations in cancer epidemiology. IARC Sci. Publ. 142, 159–184. An, F. Q., Matsuda, M., Fujii, H., Tang, R. F., Amemiya, H., Dai, Y. M., and Matsumoto, Y. (2001). Tumor heterogeneity in small hepatocellular carcinoma: Analysis of tumor cell proliferation, expression and mutation of p53 AND beta-catenin. Int. J. Cancer 93, 468–474. Anna, C. H., Sills, R. C., Foley, J. F., Stockton, P. S., Ton, T. V., and Devereux, T. R. (2000). Beta-catenin mutations and protein accumulation in all hepatoblastomas examined from B6C3F1 mice treated with anthraquinone or oxazepam. Cancer Res. 60, 2864–2868.

Candrian, U., You, M., Goodrow, T., Maronpot, R. R., Reynolds, S. H., and Anderson, M. W. (1991). Activation of protooncogenes in spontaneously occurring non-liver tumors from C57BL/6 x C3H F1 mice. Cancer Res. 51, 1148–1153. Cariello, N. F., Keohavong, P., Kat, A. G., and Thilly, W. G. (1990). Molecular analysis of complex human cell populations: Mutational spectra of MNNG and ICR-191. Mutat. Res. 231, 165–176. Challen, C., Lunec, J., Warren, W., Collier, J., and Bassendine, M. F. (1992). Analysis of the p53 tumor-suppressor gene in hepatocellular carcinomas from Britain. Hepatology 16, 1362–1366.

Aydinlik, H., Nguyen, T. D., Moennikes, O., Buchmann, A., and Schwarz, M. (2001). Selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of beta-catenin-mutated mouse liver tumors. Oncogene 20, 7812–7816.

Chao, H. K., Tsai, T. F., Lin, C. S., and Su, T. S. (1999). Evidence that mutational activation of the ras genes may not be involved in aflatoxin B(1)induced human hepatocarcinogenesis, based on sequence analysis of the ras and p53 genes. Mol. Carcinog. 26, 69–73.

Bai, F., Nakanishi, Y., Takayama, K., Pei, X. H., Inoue, K., Harada, T., Izumi, M., and Hara, N. (2003). Codon 64 of K-ras gene mutation pattern in hepatocellular carcinomas induced by bleomycin and 1-nitropyrene in A/J mice. Teratog. Carcinog. Mutagen (Suppl. 1), 161–170.

Chen, B., Liu, L., Castonguay, A., Maronpot, R. R., Anderson, M. W., and You, M. (1993). Dose-dependent ras mutation spectra in N-nitrosodiethylamine induced mouse liver tumors and 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone induced mouse lung tumors. Carcinogenesis 14, 1603–1608.

Bai, F., Nakanishi, Y., Takayama, K., Pei, X. H., Tokiwa, H., and Hara, N. (1998). Ki-ras mutation and cell proliferation of lung lesions induced by 1-nitropyrene in A/J mice. Mol. Carcinog. 22, 258–264.

Chen, B., You, L., Wang, Y., Stoner, G. D., and You, M. (1994). Allele-specific activation and expression of the K-ras gene in hybrid mouse lung tumors induced by chemical carcinogens. Carcinogenesis 15, 2031–2035.

Balmain, A. (2002). Cancer as a complex genetic trait: Tumor susceptibility in humans and mouse models. Cell 108, 145–152.

Cooper, C. A., Carby, F. A., Bubb, V. J., Lamb, D., Kerr, K. M., and Wyllie, A. H. (1997). The pattern of K-ras mutation in pulmonary adenocarcinoma

GENETIC ALTERATIONS IN LIVER AND LUNG TUMORS defines a new pathway of tumour development in the human lung. J. Pathol. 181, 401–404. Cooper, C. A., Bubb, V. J., Smithson, N., Carter, R. L., Gledhill, S., Lamb, D., Wyllie, A. H., and Carey, F. A. (1996). Loss of heterozygosity at 5q21 in nonsmall cell lung cancer: A frequent event but without evidence of apc mutation. J. Pathol. 180, 33–37. Czene, K., Lichtenstein, P., and Hemminki, K. (2002). Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. Int. J. Cancer 99, 260–266. Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., et al. (2002). Mutations of the BRAF gene in human cancer. Nature 417, 949–954. De Benedetti, V. M., Welsh, J. A., Trivers, G. E., Harpster, A., Parkinson, A. J., Lanier, A. P., McMahon, B. J., and Bennett, W. P. (1995). p53 is not mutated in hepatocellular carcinomas from Alaska Natives. Cancer Epidemiol. Biomarkers Prev. 4, 79–82. Delclos, K. B., el-Bayoumy, K., Casciano, D. A., Walker, R. P., Kadlubar, F. F., Hecht, S. S., Shivapurkar, J., Mandal, S., and Stoner, G. D. (1989). Metabolic activation of 6-nitrochrysene in explants of human bronchus and in isolated rat hepatocytes. Cancer Res. 49, 2909–2913. Demokan, S., Demir, D., Suoglu, Y., Kiyak, E., Akar, U., and Dalay, N. (2005). Polymorphisms of the XRCC1 DNA repair gene in head and neck cancer. Pathol. Oncol. Res. 11, 22–25.

413

Festing, M. F. W., Lin, L., Devereux, T. R., et al. (1998). At least four loci and gender are associated with susceptibility to the chemical induction of lung adenomas in A/J3Balb/c mice. Genomics 53, 129–136. Fox, T. R., Schumann, A. M., Watanabe, P. G., Yano, B. L., Maher, V. M., and McCormick, J. J. (1990). Mutational analysis of the H-ras oncogene in spontaneous C57BL/6 x C3H/He mouse liver tumors and tumors induced with genotoxic and nongenotoxic hepatocarcinogens. Cancer Res. 50, 4014–4019. Frey, S., Buchmann, A., Bursch, W., Schulte-Hermann, R., and Schwarz, M. (2000). Suppression of apoptosis in C3H mouse liver tumors by activated Ha-ras oncogene. Carcinogenesis 21, 161–166. Fujimoto, Y., Hampton, L. L., Wirth, P. J., Wang, N. J., Xie, J. P., and Thorgeirsson, S. S. (1994). Alterations of tumor suppressor genes and allelic losses in human hepatocellular carcinomas in China. Cancer Res. 54, 281–285. Goldblum, J. R., Bartos, R. E., Carr, K. A., and Frank, T. S. (1993). Hepatitis B and alterations of the p53 tumor suppressor gene in hepatocellular carcinoma. Am. J. Surg. Pathol. 17, 1244–1251. Gotoh, J., Obata, M., Yoshie, M., Kasai, S., and Ogawa, K. (2003). Cyclin D1 over-expression correlates with beta-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3 beta and ERK1/2 in mouse hepatic carcinogenesis. Carcinogenesis 24, 435–442.

Deng, Z., Ma, Y., Pan, L., and Peng, H. (1997). A molecular epidemiologic marker of hepatocellular carcinoma from aflatoxin B1 contaminated area in the southwest of Guangxi. Chin. J. Cancer Res. 9, 167–169.

Gray, D. L., Warshawsky, D., Xue, W., Nines, R., Wang, Y., Yao, R., and Stoner, G. D. (2001). The effects of a binary mixture of benzo(a)pyrene and 7Hdibenzo(c,g)carbazole on lung tumors and K-ras oncogene mutations in strain A/J mice. Exp. Lung Res. 27, 245–253.

Devereux, T. R., Anderson, M. W., and Belinsky, S. A. (1991). Role of ras protooncogene activation in the formation of spontaneous and nitrosamineinduced lung tumors in the resistant C3H mouse. Carcinogenesis 12, 299–303.

Greenblatt, M. S., Feitelson, M. A., Zhu, M., Bennett, W. P., Welsh, J. A., Jones, R., Borkowski, A., and Harris, C. C. (1997). Integrity of p53 in hepatitis B x antigen-positive and -negative hepatocellular carcinomas. Cancer Res. 57, 426–432.

Devereux, T. R., Belinsky, S. A., Maronpot, R. R., White, C. M., Hegi, M. E., Patel, A. C., Foley, J. F., Greenwell, A., and Anderson, M. W. (1993a). Comparison of pulmonary O6-methylguanine DNA adduct levels and Ki-ras activation in lung tumors from resistant and susceptible mouse strains. Mol. Carcinog. 8, 177–185.

Hayashi, H., Sugio, K., Matsumata, T., Adachi, E., Urata, K., Tanaka, S., and Sugimachi, K. (1993). The mutation of codon 249 in the p53 gene is not specific in Japanese hepatocellular carcinoma. Liver 13, 279–281.

Devereux, T. R., Foley, J. F., Maronpot, R. R., Kari, F., and Anderson, M. W. (1993b). Ras proto-oncogene activation in liver and lung tumors from B6C3F1 mice exposed chronically to methylene chloride. Carcinogenesis 14, 795–801. Diamantis, I. D., McGandy, C., Chen, T. J., Liaw, Y. F., Gudat, F., and Bianchi, L. (1994). A new mutational hot-spot in the p53 gene in human hepatocellular carcinoma. J. Hepatol. 20, 553–536. Doi, S. T., Kimura, M., and Katsuki, M. (1994). Site-specific mutation of the human c-Ha-ras transgene induced by dimethylbenzanthracene causes tissue-specific tumors in mice. Jpn. J. Cancer Res. 85, 801–807. Dote, H., Tsukuda, K., Toyooka, S., Yano, M., Pass, H. I., and Shimizu, N. (2004). Mutation analysis of the BRAF codon 599 in malignant pleural mesothelioma by enriched PCR-RFLP. Oncol. Reports 11, 361–363. Dragani, T. A., Manenti, G., Colombo, B. M., Falvella, F. S., Gariboldi, M., Pierotti, M. A., and Della Porta, G. (1991). Incidence of mutations at codon 61 of the Ha-ras gene in liver tumors of mice genetically susceptible and resistant to hepatocarcinogenesis. Oncogene 6, 333–338. Efron, B., and Ribshirani, R. (1993). An Introduction to Bootstrap. Chapman and Hall, New York, NY.

Hayashi, I., Konishi, N., Matsuda, H., Tsuzuki, T., Tao, M., Kitahori, Y., Tokuyama, T., Yoneda, T., Narita, N., and Hiass, Y. (1996). Comparative analysis of p16/CDKN2, p53 and ras gene alterations in human non-small cell lung cancers, with and without associated pulmonary asbestosis. Internat. J. Oncol. 8, 85–90. Hayashi, S., Hong, H. H., Toyoda, K., Ton, T. V., Devereux, T. R., Maronpot, R. R., Huff, J., and Sills, R. C. (2001). High frequency of ras mutations in forestomach and lung tumors of B6C3F1 mice exposed to 1-amino-2,4dibromoanthraquinone for 2 years. Toxicol. Pathol. 29, 422–429. Hayashi, S. M., Ton, T. V., Hong, H. H., Irwin, R. D., Haseman, J. K., Devereux, T. R., and Sills, R. C. (2003). Genetic alterations in the Catnb gene but not the H-ras gene in hepatocellular neoplasms and hepatoblastomas of B6C3F(1) mice following exposure to diethanolamine for 2 years. Chem. Biol. Interact. 146, 251–261. Hegi, M. E., Soderkvist, P., Foley, J. F., Schoonhoven, R., Swenberg, J. A., Kari, F., Maronpot, R., Anderson, M. W., and Wiseman, R. W. (1993). Characterization of p53 mutations in methylene chloride-induced lung tumors from B6C3F1 mice. Carcinogenesis 14, 803–810. Hermeking, H. (2003). Serial analysis of gene expression and cancer. Curr. Opin. Oncol. 15, 44–49. Herreno-Saenz, D., Evans, F. E., Beland, F. A., and Fu, P. P. (1995). Identification of two N2-deoxyguanosinyl DNA adducts upon nitroreduction of the environmental mutagen 1-nitropyrene. Chem. Res. Toxicol. 8, 269–277.

Enomoto, T., Weghorst, C. M., Ward, J. M., Anderson, L. M., Perantoni, A. O., and Rice, J. M. (1993). Low frequency of H-ras activation in naturally occurring hepatocellular tumors of C3H/HeNCr mice. Carcinogenesis 14, 1939–1944.

Herzog, C. R., Schut, H. A., Maronpot, R. R., and You, M. (1993). ras mutations in 2-amino-3-methylimidazo-[4,5-f]quinoline-induced tumors in the CDF1 mouse. Mol. Carcinog. 8, 202–207.

Festing, M. F. W. (1995). Use of a multistrain assay could improve the NTP Carcinogenesis bioassay. Environ. Health. Persp. 103, 44–52.

Hollstein, M., Marion, M. J., Lehman, T., Welsh, J., Harris, C. C., MartelPlanche, G., Kusters, I., and Montesano, R. (1994). p53 Mutations at A:T

414

JACKSON ET AL.

base pairs in angiosarcomas of vinyl chloride-exposed factory workers. Carcinogenesis 15, 1–3.

not differ between ras-mutated and ras-wild-type lesions. Hepatology 27, 1081–1088.

Hollstein, M. C., Wild, C. P., Bleicher, F., Chutimataewin, S., Harris, C. C., Srivatanakul, P., and Montesano, R. (1993). p53 Mutations and aflatoxin B1 exposure in hepatocellular carcinoma patients from Thailand. Int. J. Cancer 53, 51–55.

Kar, S., Jaffe, R., and Carr, B. I. (1993). Mutation at codon 249 of p53 gene in a human hepatoblastoma. Hepatology 18, 566–569.

Hong, H. H., Devereux, T. R., Roycroft, J. H., Boorman, G. A., and Sills, R. C. (1998). Frequency of ras mutations in liver neoplasms from B6C3F1 mice exposed to tetrafluoroethylene for two years. Toxicol. Pathol. 26, 646–650. Hoque, A., Patt, Y. Z., Yoffe, B., Groopman, J. D., Greenblatt, M. S., Zhang, Y. J., and Santella, R. M. (1999). Does aflatoxin B1 play a role in the etiology of hepatocellular carcinoma in the United States? Nutr. Cancer 35, 27–33. Horii, A., Nakatsuru, S., Miyoshi, Y., Ichii, S., Nagase, H., Ando, H., Yanagisawa, A., Tsuchiya, E., Kato, Y., and Nakamura, Y. (1992). Frequent somatic mutations of the APC gene in human pancreatic cancer. Cancer Res. 52, 6696–6698. Horio, Y., Chen, A., Rice, P., Roth, J. A., Malkinson, A. M., and Schrump, D. S. (1996). Ki-ras and p53 mutations are early and late events, respectively, in urethane-induced pulmonary carcinogenesis in A/J mice. Mol. Carcinog. 17, 217–223. Hosono, S., Chou, M. J., Lee, C. S., and Shih, C. (1993). Infrequent mutation of p53 gene in hepatitis B virus positive primary hepatocellular carcinomas. Oncogene 8, 491–496. Hsia, C. C., Nakashima, Y., Thorgeirsson, S. S., Harris, C. C., Minemura, M., Momosaki, S., Wang, N. J., and Tabor, E. (2000). Correlation of immunohistochemical staining and mutations of p53 in human hepatocellular carcinoma. Oncol. Rep. 7, 353–356. Hsieh, D. P., and Atkinson, D. N. (1995). Recent aflatoxin exposure and mutation at codon 249 of the human p53 gene: Lack of association. Food Addit. Contam. 12, 421–424. Hsu, I. C., Metcalf, R. A., Sun, T., Welsh, J. A., Wang, N. J., and Harris, C. C. (1991). Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350, 427–428. Huang, H., Ushijima, T., Nagao, M., Sugimura, T., and Ohgaki, H. (2003). Beta-catenin mutations in liver tumors induced by 2-amino-3,4-dimethylimidazo[4,5-f]quinoline in CDF1 mice. Cancer Lett. 198, 29–35. Husgafvel-Pursiainen, K., Hackman, P., Ridanpaa, M., Anttila, S., Karjalainen, A., Partanen, T., Taikina-Aho, O., Heikkila, L., and Vainio, H. (1993). K-ras mutations in human adenocarcinoma of the lung: Association with smoking and occupational exposure to asbestos. Int. J. Cancer 53, 250–256. Iida, M., Iwata, H., Inoue, H., Enomoto, M., Horie, N., and Takeishi, K. (2000). Correlation between Bcl-2 overexpression and H-ras mutation in naturally occurring hepatocellular proliferative lesions of the B6C3F1 mouse. Toxicol. Sci. 56, 297–302. Jemal, A., Murray, T., Ward, E., Samuels, A., Tiwari, R. C., Ghafoor, A., Feuer, E. J., and Thun, M. J. (2005). Cancer statistics, 2005. CA Cancer J. Clin. 55, 10–30. Jin, Y., Abe, K., Sato, Y., Aita, K., Irie, H., and Shiga, J. (2002). Hepatitis B and C virus infection and p53 mutations in human hepatocellular carcinoma in Harbin, Heilongjian Province, China. Hepatol. Res. 24, 379–384. Johansson, E., Reynolds, S., Anderson, M., and Maronpot, R. (1997). Frequency of Ha-ras-1 gene mutations inversely correlated with furan dose in mouse liver tumors. Mol. Carcinog. 18, 199–205. Jones, P. A. (2005). Overview of cancer epigenetics. Semin. Hematol. 42, S3–S8. Kalkuhl, A., Kaestner, K., Buchmann, A., and Schwarz, M. (1996). Expression of hepatocyte-enriched nuclear transcription factors in mouse liver tumours. Carcinogenesis 17, 609–612. Kalkuhl, A., Troppmair, J., Buchmann, A., Stinchcombe, S., Buenemann, C. L., Rapp, U. R., Kaestner, K., and Schwarz, M. (1998). p21Ras downstream effectors are increased in activity or expression in mouse liver tumors but do

Karachristos, A., Liloglou, T., Field, J. K., Deligiorgi, E., Kouskouni, E., and Spandidos, D. A. (1999). Microsatellite instability and p53 mutations in hepatocellular carcinoma. Mol. Cell. Biol. Res. Commun. 2, 155–161. Karasaki, H., Obata, M., Ogawa, K., and Lee, G. H. (1997). Roles of the Pas1 and Par2 genes in determination of the unique, intermediate susceptibility of BALB/cByJ mice to urethane-induction of lung carcinogenesis: Differential effects on tumor multiplicity, size and Kras2 mutations. Oncogene 15, 1833–1840. Katiyar, S., Dash, B. C., Thakur, V., Guptan, R. C., Sarin, S. K., and Das, B. C. (2000). p53 Tumor suppressor gene mutations in hepatocellular carcinoma patients in India. Cancer 88, 1565–1573. Kawano, R., Nishisaka, T., Takeshima, Y., Yonehara, S., and Inai, K. (1995). Role of point mutation of the K-ras gene in tumorigenesis of B6C3F1 mouse lung lesions induced by urethane. Jpn. J. Cancer Res. 86, 802–810. Kawano, R., Takeshima, Y., and Inai, K. (1996). Effects of K-ras gene mutations in the development of lung lesions induced by 4-(N-methyl-nnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mice. Jpn. J. Cancer Res. 87, 44–50. Kazachkov, Y., Khaoustov, V., Yoffe, B., Solomon, H., Klintmalm, G. B., and Tabor, E. (1996). p53 Abnormalities in hepatocellular carcinoma from United States patients: Analysis of all 11 exons. Carcinogenesis 17, 2207–2212. Kennedy, S. M., Macgeogh, C., Jaffe, R., and Spurr, N. K. (1994). Overexpression of the oncoprotein p53 in primary hepatic tumors of childhood does not correlate with gene mutations. Hum. Pathol. 25, 438–442. Keohavong, P., Mady, H. H., Gao, W. M., Siegfried, J. M., Luketich, J. D., and Melhem, M. F. (2001). Topographic analysis of K-ras mutations in histologically normal lung tissues and tumours of lung cancer patients. Br. J. Cancer 85, 235–241. Khoury, M. J., Davis, R., Gwinn, M., Lindegren, M. L., and Yoon, P. (2005). Do we need genomic research for prevention of common diseases w/ environmental causes? Am. J. Epidemiol. 161, 799–805. Kishimoto, Y., Murakami, Y., Shiraishi, M., Hayashi, K., and Sekiya, T. (1992). Aberrations of the p53 tumor suppressor gene in human non-small cell carcinomas of the lung. Cancer Res. 52, 4799–4804. Kitamura, F., Araki, S., Tanigawa, T., Miura, H., Akabane, H., and Iwasaki, R. (1998). Assessment of mutations of Ha- and Ki-ras oncogenes and the p53 suppressor gene in seven malignant mesothelioma patients exposed to asbestos–PCR-SSCP and sequencing analyses of paraffin-embedded primary tumors. Ind. Health 36, 52–56. Kress, S., Jahn, U. R., Buchmann, A., Bannasch, P., and Schwarz, M. (1992). p53 Mutations in human hepatocellular carcinomas from Germany. Cancer Res. 52, 3220–3223. Kubicka, S., Trautwein, C., Schrem, H., Tillmann, H., and Manns, M. (1995). Low incidence of p53 mutations in European hepatocellular carcinomas with heterogeneous mutation as a rare event. J. Hepatol. 23, 412–419. Lai, M. Y., Chang, H. C., Li, H. P., Ku, C. K., Chen, P. J., Sheu, J. C., Huang, G. T., Lee, P. H., and Chen, D. S. (1993). Splicing mutations of the p53 gene in human hepatocellular carcinoma. Cancer Res. 53, 1653–1656. Laurent-Puig, P., Legoix, P., Bluteau, O., Belghiti, J., Franco, D., Binot, F., Monges, G., Thomas, G., Bioulac-Sage, P., and Zucman-Rossi, J. (2001). Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology 120, 1763–1773. Lee, G. H., and Drinkwater, N. R. (1995). Hepatocarcinogenesis in BXH recombinant inbred strains of mice: Analysis of diverse phenotypic effects of the hepatocarcinogen sensitivity loci. Mol. Carcinog. 14, 190–197. Lee, S. J., Lee, S. Y., Jeon, H. S., Park, S. H., Jang, J. S., Lee, G. Y., Son, J. W., Kim, C. H., Lee, W. K., Kam, S., et al. (2005). Vascular endothelial growth

GENETIC ALTERATIONS IN LIVER AND LUNG TUMORS factor gene polymorphisms and risk of primary lung cancer. Cancer Epidemiol. Biomarkers Prev. 14, 571–575. Lee, S. N., Park, C. K., Sung, C. O., Choi, J. S., Oh, Y. L., Cho, J. W., and Yoo, B. C. (2002). Correlation of mutation and immunohistochemistry of p53 in hepatocellular carcinomas in Korean people. J. Korean Med. Sci. 17, 801–805. Li, D., Cao, Y., He, L., Wang, N. J., and Gu, J. R. (1993). Aberrations of p53 gene in human hepatocellular carcinoma from China. Carcinogenesis 14, 169–173. Lichtenstein, P., Holm, N. V., Verkasalo, P. K., Iliadou, A., Kaprio, J., Koskenvuo, M., Pukkala, E., Skytthe, A., and Hemminki, K. (2000). Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. New Engl. J. Med. 343, 78–85. Lin, L., Festing, M. F., Devereux, T. R., Crist, K. A., Christiansen, S. C., Wang, Y., Yang, A., Svenson, K., Paigen, B., Malkinson, A. M., et al. (1998). Additional evidence that the K-ras protooncogene is a candidate for the major mouse pulmonary adenoma susceptibility (Pas-1) gene. Exp. Lung Res. 24, 481–497. Lord, P. G., Hardaker, K. J., Loughlin, J. M., Marsden, A. M., and Orton, T. C. (1992). Point mutation analysis of ras genes in spontaneous and chemically induced C57Bl/10J mouse liver tumours. Carcinogenesis 13, 1383–1387. Lunn, R. M., Zhang, Y. J., Wang, L. Y., Chen, C. J., Lee, P. H., Lee, C. S., Tsai, W. Y., and Santella, R. M. (1997). p53 mutations, chronic hepatitis B virus infection, and aflatoxin exposure in hepatocellular carcinoma in Taiwan. Cancer Res. 57, 3471–3477. Maeshima, A., Miyagi, A., Hirai, T., and Nakajima, T. (1997). Mucinproducing adenocarcinoma of the lung, with special reference to goblet cell type adenocarcinoma: Immunohistochemical observation and Ki-ras gene mutation. Pathol. Int. 47, 454–460. Maeshima, A., Sakamoto, M., and Hirohashi, S. (2002). Mixed mucinous-type and non-mucinous-type adenocarcinoma of the lung: Immunohistochemical examination and K-ras gene mutation. Virchows Arch. 440, 598–603. Malarkey, D. E., Devereux, T. R., Dinse, G. E., Mann, P. C., and Maronpot, R. R. (1995). Hepatocarcinogenicity of chlordane in B6C3F1 and B6D2F1 male mice: Evidence for regression in B6C3F1 mice and carcinogenesis independent of ras proto-oncogene activation. Carcinogenesis 16, 2617–2625. Manam, S., Shinder, G. A., Joslyn, D. J., Kraynak, A. R., Hammermeister, C. L., Leander, K. R., Ledwith, B. J., Prahalada, S., van Zwieten, M. J., and Nichols, W. W. (1995). Dose-related changes in the profile of ras mutations in chemically induced CD-1 mouse liver tumors. Carcinogenesis 16, 1113–1119. Manam, S., Storer, R. D., Prahalada, S., Leander, K. R., Kraynak, A. R., Hammermeister, C. L., Joslyn, D. J., Ledwith, B. J., van Zwieten, M. J., Bradley, M. O., et al. (1992a). Activation of the Ki-ras gene in spontaneous and chemically induced lung tumors in CD-1 mice. Mol. Carcinog. 6, 68–75. Manam, S., Storer, R. D., Prahalada, S., Leander, K. R., Kraynak, A. R., Ledwith, B. J., van Zwieten, M. J., Bradley, M. O., and Nichols, W. W. (1992b). Activation of the Ha-, Ki-, and N-ras genes in chemically induced liver tumors from CD-1 mice. Cancer Res. 52, 3347–3352. Manenti, G., Falvella, F. S., Gariboldi, M., Dragani, T. A., and Pierotti, M. A. (1995). Different susceptibility to lung tumorigenesis in mice with an identical Kras2 intron 2. Genomics 29, 438–444. Manjanatha, M. G., Li, E. E., Fu, P. P., and Heflich, R. H. (1996). H- and K-ras mutational profiles in chemically induced liver tumors from B6C3F1 and CD-1 mice. J. Toxicol. Environ. Health. 47, 195–208. Mao, L., Hruban, R. H., Boyle, J. O., Tockman, M., and Sidransky, D. (1994). Detection of oncogene mutations in sputum precedes diagnosis of lung cancer. Cancer Res. 54, 1634–1637.

415

Maronpot, R. R., Fox, T., Malarkey, D. E., and Goldsworthy, T. (1995). Mutations in the ras proto-oncogene: Clues to etiology and molecular pathogenesis of mouse liver tumors. Toxicology 101, 125–156. Mass, M. J., Abu-Shakra, A., Roop, B. C., Nelson, G., Galati, A. J., Stoner, G. D., Nesnow, S., and Ross, J. A. (1996). Benzo[b]fluoranthene: Tumorigenicity in strain A/J mouse lungs, DNA adducts and mutations in the Ki-ras oncogene. Carcinogenesis 17, 1701–1704. Mass, M. J., Jeffers, A. J., Ross, J. A., Nelson, G., Galati, A. J., Stoner, G. D., and Nesnow, S. (1993). Ki-ras oncogene mutations in tumors and DNA adducts formed by benz[j]aceanthrylene and benzo[a]pyrene in the lungs of strain A/J mice. Mol. Carcinog. 8, 186–192. Massey, T. E., Devereux, T. R., Maronpot, R. R., Foley, J. F., and Anderson, M. W. (1995). High frequency of K-ras mutations in spontaneous and vinyl carbamate-induced lung tumors of relatively resistant B6CF1 (C57BL/6J x BALB/cJ) mice. Carcinogenesis 16, 1065–1069. Matzinger, S. A., Crist, K. A., Stoner, G. D., Anderson, M. W., Pereira, M. A., Steele, V. E., Kelloff, G. J., Lubet, R. A., and You, M. (1995). K-ras mutations in lung tumors from A/J and A/J x TSG-p53 F1 mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and phenethyl isothiocyanate. Carcinogenesis 16, 2487–2492. Matzinger, S. A., Gunning, W. T., You, M., and Castonguay, A. (1994). Ki-ras mutations in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone- initiated and butylated hydroxytoluene-promoted lung tumors in A/J mice. Mol. Carcinog. 11, 42–48. McCullagh, P., and Nelder, J. (1997). Generalized Linear Models. Chapman and Hall, New York, NY. Miller, C. W., Simon, K., Aslo, A., Kok, K., Yokota, J., Buys, C. H., Terada, M., and Koeffler, H. P. (1992). p53 mutations in human lung tumors. Cancer Res. 52, 1695–1698. Mitchell, K. R., and Warshawsky, D. (1999). Frequent Ha-ras mutations in murine skin and liver tumors induced by 7H-dibenzo[c,g]carbazole. Mol. Carcinog. 25, 107–112. Mitsudomi, T., Lam, S., Shirakusa, T., and Gazdar, A. F. (1993). Detection and sequencing of p53 gene mutations in bronchial biopsy samples in patients with lung cancer. Chest 104, 362–365. Mor, O., Yaron, P., Huszar, M., Yellin, A., Jakobovitz, O., Brok-Simoni, F., Rechavi, G., and Reichert, N. (1997). Absence of p53 mutations in malignant mesotheliomas. Am. J. Respir. Cell Mol. Biol. 16, 9–13. Mori, I., Hayashi, S., Horinouchi, A., Nonoyama, T., and Miyajima, H. (1995). Point mutations at codon 61 of the c-H-RAS gene detected in paraffin sections of spontaneous hepatocellular tumors in aged B6C3F1 mice. J. Toxicol. Pathol. 8, 123–128. Murakami, Y., Hayashi, K., Hirohashi, S., and Sekiya, T. (1991). Aberrations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas. Cancer Res. 51, 5520–5525. Naito, M., Satake, M., Sakai, E., Hirano, Y., Tsuchida, N., Kanzaki, H., Ito, Y., and Mori, T. (1992). Detection of p53 gene mutations in human ovarian and endometrial cancers by polymerase chain reaction-single strand conformation polymorphism analysis. Jpn. J. Cancer Res. 83, 1030–1036. Naoki, K., Chen, T. H., Richards, W. G., Sugarbaker, D. J., and Meyerson, M. (2002). Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res. 62, 7001–7003. Nelson, H. H., Christiani, D. C., Wiencke, J. K., Mark, E. J., Wain, J. C., and Kelsey, K. T. (1999). K-ras mutation and occupational asbestos exposure in lung adenocarcinoma: Asbestos-related cancer without asbestosis. Cancer Res. 59, 4570–4573. Nesnow, S., Ross, J. A., Nelson, G., Wilson, K., Roop, B. C., Jeffers, A. J., Galati, A. J., Stoner, G. D., Sangaiah, R., Gold, A., et al. (1994). Cyclopenta[cd]pyrene-induced tumorigenicity, Ki-ras codon 12 mutations and DNA adducts in strain A/J mouse lung. Carcinogenesis 15, 601–606.

416

JACKSON ET AL.

Ng, I. O., Chung, L. P., Tsang, S. W., Lam, C. L., Lai, E. C., Fan, S. T., and Ng, M. (1994a). p53 Gene mutation spectrum in hepatocellular carcinomas in Hong Kong Chinese. Oncogene 9, 985–990. Ng, I. O., Srivastava, G., Chung, L. P., Tsang, S. W., and Ng, M. M. (1994b). Overexpression and point mutations of p53 tumor suppressor gene in hepatocellular carcinomas in Hong Kong Chinese people. Cancer 74, 30–37. Ni, Z., Liu, Y., Keshava, N., Zhou, G., Whong, W., and Ong, T. (2000). Analysis of K-ras and p53 mutations in mesotheliomas from humans and rats exposed to asbestos. Mutat. Res. 468, 87–92. Nishida, N., Fukuda, Y., Kokuryu, H., Toguchida, J., Yandell, D. W., Ikenega, M., Imura, H., and Ishizaki, K. (1993). Role and mutational heterogeneity of the p53 gene in hepatocellular carcinoma. Cancer Res. 53, 368–372. Nose, H., Imazeki, F., Ohto, M., and Omata, M. (1993). p53 Gene mutations and 17p allelic deletions in hepatocellular carcinoma from Japan. Cancer 72, 355–360. Nuzum, E. O., Malkinson, A. M., and Beer, D. G. (1990). Specific Ki-ras codon 61 mutations may determine the development of urethan-induced mouse lung adenomas or adenocarcinomas. Mol. Carcinog. 3, 287–295. Oda, T., Tsuda, H., Scarpa, A., Sakamoto, M., and Hirohashi, S. (1992a). p53 Gene mutation spectrum in hepatocellular carcinoma. Cancer Res. 52, 6358–6364. Oda, T., Tsuda, H., Scarpa, A., Sakamoto, M., and Hirohashi, S. (1992b). Mutation pattern of the p53 gene as a diagnostic marker for multiple hepatocellular carcinoma. Cancer Res. 52, 3674–3678. Ogawa, K., Yamada, Y., Kishibe, K., Ishizaki, K., and Tokusashi, Y. (1999). Beta-catenin mutations are frequent in hepatocellular carcinomas but absent in adenomas induced by diethylnitrosamine in B6C3F1 mice. Cancer Res. 59, 1830–1833. Ohmori, H., Abe, T., Hirano, H., Murakami, T., Katoh, T., Gotoh, S., Kido, M., Kuroiwa, A., Nomura, T., and Higashi, K. (1992). Comparison of Ki-ras gene mutation among simultaneously occurring multiple urethan-induced lung tumors in individual mice. Carcinogenesis 13, 851–855. Olivier, M., Eeles, R., Hollstein, M., Khan, M. A., Harris, C. C., and Hainaut, P. (2002). The IARC TP53 database: New online mutation analysis and recommendations to users. Hum. Mutat. 19, 607–614. Oreffo, V. I., Robinson, S., You, M., Wu, M. C., and Malkinson, A. M. (1998). Decreased expression of the adenomatous polyposis coli (Apc) and mutated in colorectal cancer (Mcc) genes in mouse lung neoplasia. Mol. Carcinogen. 21, 37–49. Ozturk, M. (1991). p53 mutation in hepatocellular carcinoma after aflatoxin exposure. Lancet 338, 1356–1359. Pan, H., Califano, J., Ponte, J. F., et al. (2005). Loss of heterozygosity patterns provide fingerprints for genetic heterogeneity in multistep cancer progression of tobacco smoke-induced non-small cell lung cancer. Cancer Res. 65, 1664–1669. Park, Y. M., Yoo, Y. D., Han, K. H., Chun, J. Y., Kang, J. K., and Park, I. S. (1996). Mutation of tumor suppressor gene p53 in hepatocellular carcinomas from Korea. Exp. Mol. Med. 28, 173–179. Philips, D. H., Hewer, A., Osborne, M. R., Cole, K. J., Churchill, C., and Arlt, V. M. (2005). Organ specificity of DNA adduct formation by tamoxifen and a-hydroxytamoxifen in the rat: Implications for understanding the mechanism(s) of tamoxifen carcinogenicity and for human risk assessment. Mutagenesis 20, 297–303. Pogribny, I. P., and James, S. J. (2002). Reduction of p53 gene expression in human primary hepatocellular carcinoma is associated with promoter region methylation without coding region mutation. Cancer Lett. 176, 169–174. Prahalad, A. K., Ross, J. A., Nelson, G. B., Roop, B. C., King, L. C., Nesnow, S., and Mass, M. J. (1997). DibenzoþAFs-a,lþAF0-pyrene-induced DNA adduction, tumorigenicity, and Ki-ras oncogene mutations in strain A/J mouse lung. Carcinogenesis 18, 1955–1963.

Prevo, L. J., Sanchez, C. A., Galipeau, P. C., and Reid, B. J. (1999). p53-mutant clones and field effects in Barrett’s esophagus. Cancer Res. 59, 4784–4787. Ramakrishna, G., Bialkowska, A., Perella, C., Birely, L., Fornwald, L. W., Diwan, B. A., Shiao, Y. H., and Anderson, L. M. (2000). Ki-ras and the characteristics of mouse lung tumors. Mol. Carcinog. 28, 156–167. Ramakrishna, G., Perella, C., Birely, L., Diwan, B. A., Fornwald, L. W., and Anderson, L. M. (2002). Decrease in K-ras p21 and increase in Raf1 and activated Erk 1 and 2 in murine lung tumors initiated by N-nitrosodimethylamine and promoted by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 179, 21–34. Rashid, A., Wang, J. S., Qian, G. S., Lu, B. X., Hamilton, S. R., and Groopman, J. D. (1999). Genetic alterations in hepatocellular carcinomas: Association between loss of chromosome 4q and p53 gene mutations. Br. J. Cancer 80, 59–66. Re, F. C., Manenti, G., Borrello, M. G., Colombo, M. P., Fisher, J. H., Pierotti, M. A., Della Porta, G., and Dragani, T. A. (1992). Multiple molecular alterations in mouse lung tumors. Mol. Carcinog. 5, 155–160. Redondo, M., Rodriguez, F., Hortas, M. L., Concha, A., Morell, M., Garrido, F., and Ruiz-Cabello, F. (1997). Lack of correlation between codon 12 K-ras mutations and major histocompatibility complex antigens in bronchogenic carcinomas. Cancer Detect. Prev. 21, 412–417. Reichel, M. B., Ohgaki, H., Petersen, I., and Kleihues, P. (1994). p53 mutations in primary human lung tumors and their metastases. Mol. Carcinog. 9, 105–109. Richardson, K. K., Helvering, L. M., Copple, D. M., Rexroat, M. A., Linville, D. W., Engelhardt, J. A., Todd, G. C., and Richardson, F. C. (1992a). Genetic alterations in the 61st codon of the H-ras oncogene isolated from archival sections of hepatic hyperplasias, adenomas and carcinomas in control groups of B6C3F1 mouse bioassay studies conducted from 1979 to 1986. Carcinogenesis 13, 935–941. Richardson, K. K., Rexroat, M. A., Helvering, L. M., Copple, D. M., and Richardson, F. C. (1992b). Temporal changes in the mutant frequency and mutation spectra of the 61st codon of the H-ras oncogene following exposure of B6C3F1 mice to N-nitrosodiethylamine (DEN). Carcinogenesis 13, 1277–1279. Rodenhuis, S., Slebos, R. J., Boot, A. J., Evers, S. G., Mooi, W. J., Wagenaar, S. S., van Bodegom, P. C., and Bos, J. L. (1988). Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res. 48, 5738–5741. Rodenhuis, S., van de Wetering, M. L., Mooi, W. J., Evers, S. G., van Zandwijk, N., and Bos, J. L. (1987). Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N. Engl. J. Med. 317, 929–935. Ronai, Z. A., Gradia, S., Peterson, L. A., and Hecht, S. S. (1993). G to A transitions and G to T transversions in codon 12 of the Ki-ras oncogene isolated from mouse lung tumors induced by 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK) and related DNA methylating and pyridyloxobutylating agents. Carcinogenesis 14, 2419–2422. Rumsby, P. C., Barrass, N. C., Phillimore, H. E., and Evans, J. G. (1991). Analysis of the Ha-ras oncogene in C3H/He mouse liver tumours derived spontaneously or induced with diethylnitrosamine or phenobarbitone. Carcinogenesis 12, 2331–2336. Sahoo, T., Ramakrishna, B., Habibullah, C. M., Patil, D. N., and Das, M. R. (1993). p53 Mutation in human hepatocellular carcinoma in India. Curr. Sci. (Bangalore) 65, 554–557. Sameshima, Y., Matsuno, Y., Hirohashi, S., Shimosato, Y., Mizoguchi, H., Sugimura, T., Terada, M., and Yokota, J. (1992). Alterations of the p53 gene are common and critical events for the maintenance of malignant phenotypes in small-cell lung carcinoma. Oncogene 7, 451–457. Sanchez-Cespedes, M., Reed, A. L., Buta, M., Wu, L., Westra, W. H., Herman, J. G., Yang, S. C., Jen, J., and Sidransky, D. (1999). Inactivation of the

GENETIC ALTERATIONS IN LIVER AND LUNG TUMORS

417

INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancer. Oncogene 18, 5843–5849.

tumors of hepatocarcinogenesis- resistant strains of mice. Carcinogenesis 13, 2427–2433.

Schroeder, M., DeAngelo, A. B., and Mass, M. J. (1997). Dichloroacetic acid reduces Ha-ras codon 61 mutations in liver tumors from female B6C3F1 mice. Carcinogenesis 18, 1675–1678.

Stern, M. C., Umbach, D. M., Yu, M. C., London, S. J., Zhang, Z. Q., and Taylor, J. A. (2001). Hepatitis B, aflatoxin B(1), and p53 codon 249 mutation in hepatocellular carcinomas from Guangxi, People’s Republic of China, and a meta-analysis of existing studies. Cancer Epidemiol. Biomarkers Prev. 10, 617–625.

Scorsone, K. A., Zhou, Y. Z., Butel, J. S., and Slagle, B. L. (1992). p53 Mutations cluster at codon 249 in hepatitis B virus-positive hepatocellular carcinomas from China. Cancer Res. 52, 1635–1638. Segers, K., Backhovens, H., Singh, S. K., De Voecht, J., Ramael, M., Van Broeckhoven, C., and Van Marck, E. (1995). Immunoreactivity for p53 and mdm2 and the detection of p53 mutations in human malignant mesothelioma. Virchows Arch. 427, 431–436. Sheu, J. C., Huang, G. T., Lee, P. H., Chung, J. C., Chou, H. C., Lai, M. Y., Wang, J. T., Lee, H. S., Shih, L. N., Yang, P. M., et al. (1992). Mutation of p53 gene in hepatocellular carcinoma in Taiwan. Cancer Res. 52, 6098–6100. Shi, C. Y., Phang, T. W., Lin, Y., Wee, A., Li, B., Lee, H. P., and Ong, C. N. (1995). Codon 249 mutation of the p53 gene is a rare event in hepatocellular carcinomas from ethnic Chinese in Singapore. Br. J. Cancer 72, 146–149. Shieh, Y. S., Nguyen, C., Vocal, M. V., and Chu, H. W. (1993). Tumorsuppressor p53 gene in hepatitis C and B virus-associated human hepatocellular carcinoma. Int. J. Cancer 54, 558–562. Shimizu, Y., Zhu, J. J., Han, F., Ishikawa, T., and Oda, H. (1999). Different frequencies of p53 codon-249 hot-spot mutations in hepatocellular carcinomas in Jiang-su province of China. Int. J. Cancer 82, 187–190. Shinder, G. A., Manam, S., and Nichols, W. W. (1993). A sensitive restriction fragment length polymorphism method to detect CAA/AAA mutations at codon 61 of Ha-ras. Mol. Carcinog. 7, 263–267. Siegfried, J. M., Gillespie, A. T., Mera, R., Casey, T. J., Keohavong, P., Testa, J. R., and Hunt, J. D. (1997). Prognostic value of specific KRAS mutations in lung adenocarcinomas. Cancer Epidemiol. Biomarkers Prev. 6, 841–847. Silini, E. M., Bosi, F., Pellegata, N. S., Volpato, G., Romano, A., Nazari, S., Tinelli, C., Ranzani, G. N., Solcia, E., and Fiocca, R. (1994). K-ras gene mutations: An unfavorable prognostic marker in stage I lung adenocarcinoma. Virchows Arch. 424, 367–373. Sills, R. C., Hong, H. L., Greenwell, A., Herbert, R. A., Boorman, G. A., and Devereux, T. R. (1995). Increased frequency of K-ras mutations in lung neoplasms from female B6C3F1 mice exposed to ozone for 24 or 30 months. Carcinogenesis 16, 1623–1628. Sills, R. C., Hong, H. L., Melnick, R. L., Boorman, G. A., and Devereux, T. R. (1999). High frequency of codon 61 K-ras A–>T transversions in lung and Harderian gland neoplasms of B6C3F1 mice exposed to chloroprene (2chloro-1,3-butadiene) for 2 years, and comparisons with the structurally related chemicals isoprene and 1,3-butadiene. Carcinogenesis 20, 657–662. Slaughter, D. P., Southwick, H. W., and Smejkal, W. (1953). ‘‘Field cancerization’’ in oral stratified squamous epithelium. Cancer 6, 963–968. Slebos, R. J., Kibbelaar, R. E., Dalesio, O., Kooistra, A., Stam, J., Meijer, C. J., Wagenaar, S. S., Vanderschueren, R. G., van Zandwijk, N., Mooi, W. J., et al. (1990). K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N. Engl. J. Med. 323, 561–565. Soini, Y., Chia, S. C., Bennett, W. P., Groopman, J. D., Wang, J. S., DeBenedetti, V. M., Cawley, H., Welsh, J. A., Hansen, C., Bergasa, N. V., et al. (1996). An aflatoxin-associated mutational hotspot at codon 249 in the p53 tumor suppressor gene occurs in hepatocellular carcinomas from Mexico. Carcinogenesis 17, 1007–1012.

Stern, R. S., Bolshakov, S., Nataraj, A. J., and Ananthaswamy, H. N. (2002). p53 mutation in nonmelanoma skin cancers occurring in psoralen ultraviolet a-treated patients: Evidence for heterogeneity and field cancerization. J. Investig. Dermatol. 119, 522–526. Stowers, S. J., Glover, P. L., Reynolds, S. H., Boone, L. R., Maronpot, R. R., and Anderson, M. W. (1987). Activation of the K-ras protooncogene in lung tumors from rats and mice chronically exposed to tetranitromethane. Cancer Res. 47, 3212–3219. Stowers, S. J., Wiseman, R. W., Ward, J. M., Miller, E. C., Miller, J. A., Anderson, M. W., and Eva, A. (1988). Detection of activated protooncogenes in N-nitrosodiethylamine-induced liver tumors: A comparison between B6C3F1 mice and Fischer 344 rats. Carcinogenesis 9, 271–276. Sugio, K., Fukuyama, Y., Sakada, T., Nishioka, K., Yamazaki, K., Ushijima, C., Tsukamoto, S., Ishida, T., and Sugimachi, K. (1998). Second primary cancers after resection of lung adenocarcinoma with ras gene mutation. Anticancer Res. 18, 3395–3398. Suzuki, Y., Orita, M., Shiraishi, M., Hayashi, K., and Sekiya, T. (1990). Detection of ras gene mutations in human lung cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene 5, 1037–1043. Takahashi, T., Takahashi, T., Suzuki, H., Hida, T., Sekido, Y., Ariyoshi, Y., and Ueda, R. (1991). The p53 gene is very frequently mutated in small-cell lung cancer with a distinct nucleotide substitution pattern. Oncogene 6, 1775–1778. Tanaka, S., Toh, Y., Adachi, E., Matsumata, T., Mori, R., and Sugimachi, K. (1993). Tumor progression in hepatocellular carcinoma may be mediated by p53 mutation. Cancer Res. 53, 2884–2887. Taniguchi, Y., Gemma, A., Takeda, Y., Takenaka, K., Niitani, H., Kudoh, S., and Shimada, T. (1996). Stability of p53 tumor suppressor gene mutations during the process of metastasis and during chemotherapy. Lung Cancer 14, 219–228. Tannapfel, A., Busse, C., Weinans, L., Benicke, M., Katalinic, A., Geissler, F., Hauss, J., and Wittekind, C. (2001). INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene 20, 7104–7109. Tomizawa, Y., Kohno, T., Fujita, T., Kiyama, M., Saito, R., Noguchi, M., Matsuno, Y., Hirohashi, S., Yamaguchi, N., Nakajima, T., et al. (1999). Correlation between the status of the p53 gene and survival in patients with stage I non-small cell lung carcinoma. Oncogene 18, 1007–1014. Ton, T. V., Hong, H. H., Anna, C. H., Dunnick, J. K., Devereux, T. R., Sills, R. C., and Kim, Y. (2004). Predominant K-ras codon 12 G / A transition in chemically induced lung neoplasms in B6C3F1 Mice. Toxicol. Pathol. 32, 16–21. Top, B., Mooi, W. J., Klaver, S. G., Boerrigter, L., Wisman, P., Elbers, H. R., Visser, S., and Rodenhuis, S. (1995). Comparative analysis of p53 gene mutations and protein accumulation in human non-small-cell lung cancer. Int. J. Cancer 64, 83–91. Tseng, R. C., Change, J. W., Hsien, F. J., et al. (2005). Genomewide loss of heterozygosity and its clinical associations in non small cell lung cancer. Int. J. Cancer 117, 241–247.

Somers, V. A., Leimbach, D. A., Theunissen, P. H., Murtagh, J. J. J., Holloway, B., Ambergen, A. W., and Thunnissen, F. B. (1998). Validation of the PointEXACCT method in non-small cell lung carcinomas. Clin. Chem. 44, 1404–1409.

Unsal, H., Yakicier, C., Marcais, C., Kew, M., Volkmann, M., Zentgraf, H., Isselbacher, K. J., and Ozturk, M. (1994). Genetic heterogeneity of hepatocellular carcinoma. Proc. Natl. Acad. Sci. U.S.A. 91, 822–826.

Stanley, L. A., Devereux, T. R., Foley, J., Lord, P. G., Maronpot, R. R., Orton, T. C., and Anderson, M. W. (1992). Proto-oncogene activation in liver

Vautier, G., Bomford, A. B., Portmann, B. C., Metivier, E., Williams, R., and Ryder, S. D. (1999). p53 Mutations in British patients with hepatocellular

418

JACKSON ET AL.

carcinoma: Clustering in genetic hemochromatosis. Gastroenterology 117, 154–160.

chemically induced hepatomas of the male B6C3 F1 mouse. Proc. Natl. Acad. Sci. U.S.A. 83, 5825–5829.

Vesey, D. A., Hayward, N. K., and Cooksley, W. G. (1994). p53 gene in hepatocellular carcinomas from Australia. Cancer Detect. Prev. 18, 123–130. Volkmann, M., Schiff, J. H., Hajjar, Y., Otto, G., Stilgenbauer, F., Fiehn, W., Galle, P. R., and Hofmann, W. J. (2001). Loss of CD95 expression is linked to most but not all p53 mutants in European hepatocellular carcinoma. J. Mol. Med. 79, 594–600.

Wong, N., Lai, P., Pang, E., Fung, L. F., Sheng, Z., Wong, V., Wang, W., Hayashi, Y., Perlman, E., Yuna, S., et al. (2000). Genomic aberrations in human hepatocellular carcinomas of differing etiologies. Clin. Cancer Res. 6, 4000–4009.

Von Tungeln, L. S., Xia, Q., Bucci, T., Heflich, R. H., and Fu, P. P. (1999). Tumorigenicity and liver tumor ras-protooncogene mutations in CD-1 mice treated neonatally with 1- and 3-nitrobenzo[a]pyrene and their trans7,8-dihydrodiol and aminobenzo[a]pyrene metabolites. Cancer Lett. 137, 137–143. Wang, X., and Witschi, H. (1995). Mutations of the Ki-ras protooncogene in 3methylcholanthrene and urethan-induced and butylated hydroxytoluenepromoted lung tumors of strain A/J and SWR mice. Cancer Lett. 91, 33–39.

Xia, Q., Yi, P., Zhan, D. J., Von Tungeln, L. S., Hart, R. W., Heflich, R. H., and Fu, P. P. (1998). Liver tumors induced in B6C3F1 mice by 7-chlorobenz[a]anthracene and 7-bromobenz[a]anthracene contain K-ras protooncogene mutations. Cancer Lett. 123, 21–25. Xue, W., and Warshawsky, D. (2005). Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: A review. Toxicol. Appl. Pharm. 206, 73–93. Yanez, L., Groffen, J., and Valenzuela, D. M. (1987). c-K-ras mutations in human carcinomas occur preferentially in codon 12. Oncogene 1, 315–318.

Wang, Y., Wang, Y., Stoner, G., and You, M. (1993). ras mutations in 2acetylaminofluorene-induced lung and liver tumors from C3H/HeJ and (C3H x A/J)F1 mice. Cancer Res. 53, 1620–1624.

Yang, M., Zhou, H., Kong, R. Y., Fong, W. F., Ren, L. Q., Liao, X. H., Wang, Y., Zhuang, W., and Yang, S. (1997). Mutations at codon 249 of p53 gene in human hepatocellular carcinomas from Tongan, China. Mutat. Res. 381, 25–29.

Warshawsky, D., Talaska, G., Jaeger, M., Collins, T., Galati, A., You, L., and Stoner, G. (1996). Carcinogenicity, DNA adduct formation and K-ras activation by 7H-dibenzo[c,g]carbazole in strain A/J mouse lung. Carcinogenesis 17, 865–871.

You, L., Wang, D., Galati, A. J., Ross, J. A., Mass, M. J., Nelson, G. B., Wilson, K. H., Amin, S., Stoner, J. C., Nesnow, S., et al. (1994). Tumor multiplicity, DNA adducts and K-ras mutation pattern of 5-methylchrysene in strain A/J mouse lung. Carcinogenesis 15, 2613–2618.

Watson, M. A., Devereux, T. R., Malarkey, D. E., Anderson, M. W., and Maronpot, R. R. (1995). H-ras oncogene mutation spectra in B6C3F1 and C57BL/6 mouse liver tumors provide evidence for TCDD promotion of spontaneous and vinyl carbamate-initiated liver cells. Carcinogenesis 16, 1705–1710.

You, M., Wang, Y., Lineen, A. M., Gunning, W. T., Stoner, G. D., and Anderson, M. W. (1992b). Mutagenesis of the K-ras protooncogene in mouse lung tumors induced by N-ethyl-N-nitrosourea or N-nitrosodiethylamine. Carcinogenesis 13, 1583–1586.

Weihrauch, M., Lehnert, G., Kockerling, F., Wittekind, C., and Tannapfel, A. (2000). p53 Mutation pattern in hepatocellular carcinoma in workers exposed to vinyl chloride. Cancer 88, 1030–1036. Weihrauch, M., Markwarth, A., Lehnert, G., Wittekind, C., Wrbitzky, R., and Tannapfel, A. (2002). Abnormalities of the ARF-p53 pathway in primary angiosarcomas of the liver. Hum. Pathol. 33, 884–892. Wiseman, R. W., Stowers, S. J., Miller, E. C., Anderson, M. W., and Miller, J. A. (1986). Activating mutations of the c-Ha-ras protooncogene in

You, M., Wang, Y., Nash, B., and Stoner, G. D. (1993). K-ras mutations in benzotrichloride-induced lung tumors of A/J mice. Carcinogenesis 14, 1247–1249. You, M., Wang, Y., Stoner, G., You, L., Maronpot, R., Reynolds, S. H., and Anderson, M. (1992a). Parental bias of Ki-ras oncogenes detected in lung tumors from mouse hybrids. Proc. Natl. Acad. Sci. U.S.A. 89, 5804–5808. Zhu, M., Guangyu, G., Fangmei, L., Wenliang, W., and Yimin, D. (2002). Interaction of hepatitis B virus with tumor suppressor gene p53: Its significance and biological function. Prog. Nat. Sci. 12, 24–29.

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