Quantitative trait locus mapping of susceptibilities to butylated hydroxytoluene-induced lung tumor promotion and pulmonary inflammation in CXB mice
Alvin M. Malkinson1,4,
Richard A. Radcliffe1 and
Alison K. Bauer2,,3
1 Department of Pharmaceutical Sciences and
2 Department of Pharmacology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA
Present address: CIIT, 6 Davis Drive, Research Triangle Park, NC 27709, USA
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Abstract
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We have reported previously [Bauer,A.K. et al. (2001) Exp. Lung Res., 27, 197216] that the 13 CXB recombinant inbred mouse strains derived from BALB/cByJ and C57BL/6J progenitors vary in their responsiveness to both lung tumor promotion and pulmonary inflammation induced by chronic administration of butylated hydroxytoluene (BHT). Herein we have applied these data, along with markers known to be polymorphic among these strains, to conduct linkage analysis of these susceptibilities. This enabled us to assign provisional quantitative trait loci (QTL) that govern these strain variations in susceptibility as a genetic approach to assessing the influence of inflammation on tumorigenesis. A Chr 15 (39.155.6 cM) QTL regulated susceptibility to two-stage carcinogensis, a protocol in which chronic BHT exposure followed a single urethane injection; a similar QTL on Chr 15 (46.761.7 cM) influenced BHT induction of cyclooxygenase-2 (COX-2) expression. A Chr 18 (3741 cM) QTL modulated both the number of lung tumors induced by 3-methylcholanthrene (MCA) injection with subsequent treatment with BHT as well as BHT-induced ingress of macrophages into airways. Other chromosomal sites that affected either the degree of BHT-elicited macrophage infiltration, Chr 9 (4861 cM), or COX-2 induction, Chr 10 (5965 cM), were reported to influence susceptibility to lung tumorigenesis in other strains. The fact that common chromosomal locations regulate both inflammation and carcinogenesis suggests a pathogenic role of inflammatory mediators in tumor development that may be exploited for chemoprevention of lung cancer.
Abbreviations: BHT, butylated hydroxytoluene; BAL, bronchoalveolar lavage; COX-1, COX-2, cyclooxygenase 1 and 2; MCA, 3-methylcholanthrene; Par, pulmonary adenoma resistance; Pas, pulmonary adenoma susceptibility; QTL, quantitative trait loci; RI, recombinant inbred; U, urethane.
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Introduction
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Susceptibility to most common pathologies, including lung cancer, displays polygenic inheritance. The current lung cancer epidemic and ineffectiveness of therapies emphasize the importance of delineating candidate gene products that confer resistance, as they offer novel pre-validated targets for chemoprevention (1). Additionally, people whose tumor modifier alleles generate high risk would benefit from early screening. Genetic analysis of `lung cancer families' whose members exhibit a disproportionately high frequency of this disease has just begun (2).
Lung tumors that mice develop have histologic and molecular features similar to human pulmonary adenocarcinoma (35). This biological relevance, along with the syntenic arrangements of mouse and human genes, imminent deciphering of the mouse genome and remarkable power of genetic analysis in inbred mice, provide a model for identifying lung cancer susceptibility genes. Inbred strains vary in their susceptibilities to respiratory carcinogenesis induced by single agents (6) and two-stage protocols in which exposure to the non-carcinogen, BHT, after treatment with an initiating agent promotes lung tumor formation (7). The QTL mapping strategy for identifying genes that underlie polygenic diseases is based on polymorphic DNA markers. Over a dozen cancer modifier genes designated as Pas (Pulmonary adenoma susceptibility; 8) and Par (Pulmonary adenoma resistance; 9) have been assigned (10); genes governing a predisposition to two-stage pulmonary carcinogenesis have not yet been mapped.
Chronic pulmonary inflammatory diseases increase the risk of lung cancer (11). Glucocorticoids (12,13), non-steroidal anti-inflammatory drugs (NSAIDs) that diminish eicosanoid production (14), and depletion of endogenous and infiltrating alveolar macrophages (15) inhibit chemical induction of mouse lung tumors. Inbred strains vary in their susceptibilities to pneumotoxins and the ensuing inflammation that accompanies lung damage (16). BHT causes reversible lung injury in mice and also augments lung tumor formation, and strains vary in their responsiveness to these effects (7,15,17,18).
Several years ago (7) we showed that the CXB recombinant inbred (RI) strains derived from BALB/cBy and C57BL/6J progenitors (herein referred to as BALB and B6, respectively) differed in their susceptibilities to BHT promotion of U-initiated lung tumorigenesis. We recently extended this analysis and examined the sensitivities of these strains to BHT promotion of MCA-initiated lung tumorigenesis and to BHT-induced pulmonary inflammation (15). Figures 1 and 2
graphically summarize the data. Single-agent carcinogenesis consisted of a single urethane (U) or MCA injection, while in two-stage carcinogenesis, these U or MCA treatments were followed by multiple weekly BHT injections. Lung tumors were enumerated 5 months after the U or MCA injection. The CXB strains fell into two groups according to their U and U/BHT lung tumor multiplicities. CXB 24, 6 and 811 were BALB-like, having >2 tumors/mouse; CXB 1, 5, 7, 12 and 13 were B6-like with <0.3 tumors/mouse. CXB 4 and 9 were the only strains in which MCA alone induced >2 tumors/mouse. The tumor multiplicities elicited by an MCA/BHT protocol appeared to form a continuous distribution, and the MCA-alone tumor number was not predictive of the extent of lung tumor promotion by BHT. Phenotypes of some RI strains were outside the ranges bounded by their BALB and B6 progenitors, implying that tumor susceptibilities are polygenic in nature, as reported previously when only data for CXB 17 were available (7).

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Fig. 1. Mean ± SEM of lung tumor multiplicities in the CXB RI strains (solid bars) and their BALB and B6 progenitors (open bars) in response to different carcinogenesis regimens. Multiplicities (drawn largely from the tabular data in ref. 15) are arranged from high to low.
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Fig. 2. Fold-induction caused by BHT of five inflammatory parameters in CXB RI strains (closed bars) and their BALB and B6 progenitors (open bars). These increases over the corn oil vehicle control, drawn largely from the tabular data in ref. 15, are arranged from high to low.
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A chronic inflammatory response was induced by injecting CXB mice i.p. with either BHT or the corn oil control vehicle weekly over several weeks (15,17,18). Six days following the last injection, lungs were lavaged, BAL fluid collected, protein content in the BAL return estimated vascular permeability, and BAL titers of macrophages and lymphocytes estimated inflammatory cell infiltration. In a separate set of similarly treated mice, the lungs were perfused, homogenized and particulate fractions collected to determine concentrations of the pro-inflammatory cyclooxygenase enzymes, COX-1 and COX-2, by immunoblotting, as described (20). CXB 4 mice were resistant to BHT-induced elevations of three of the five inflammatory parameters, whereas multiple phenotypes were severely affected in CXB 2 and 12. The BALB progenitor was more sensitive to inflammation than most RI strains, but as some RI strains exhibited less inflammation than the B6 progenitor, this indicates multigenic control of these inflammatory parameters.
In this report, we apply QTL analysis to these previously demonstrated strain variations. This reveals that common loci moderate sensitivity or resistance to carcinogenesis and to injury/inflammation.
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Materials and methods
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QTL analysis
Two sets of genomic markers polymorphic among the CXB strains were available for QTL analysis, one from Jackson Laboratory (Bar Harbor, MA) (21) and a more recent set of >700 markers described by Williams et al. (22). The Jackson marker set is denser for CXB 17 than for CXB 813 as the latter six strains were derived 20 years later, whereas all markers in the Williams et al. set were used to genotype all 13 CXB RI strains. To avoid the possibility of incorrect genotype data from either of these marker sets, each phenotype was independently analyzed using both sets of genotypes in a point analysis procedure with the Map Manager QT program (23). Permutation tests were performed to establish linkage thresholds on these data sets. We report only QTL that appeared using both sets of marker data, had at least three strains represented by each parental genotype at the marker and were within the criteria of Lander and Kruglyak (24) of at least suggestive linkage (LOD > 1.9). All of the QTL that were mapped using the Williams et al. data set were also detected using the Jackson set. An additional 12 QTL (LOD > 1.9) were detected that were unique to the Jackson set. As these were not confirmed with the Williams et al. data set, we do not report them.
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Results
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Linkage analysis of lung tumor multiplicity among the CXB RI strains
Herein, we used strain variations in susceptibility to promotion of U- and MCA-initiated mice by BHT reported previously (see ref. 15) to assign QTL. Each of the four carcinogenesis protocols was modulated by at least one QTL, some of which cover a broad section of a chromosome (Table I
). In U carcinogenesis, a site on Chr 15 (39.155.6 cM) governed tumor formation both in the presence and absence of subsequent promotion by BHT. Additional QTL for susceptibility to U were found in the absence [Chr 14 (43 cM)] or presence [Chr 4 (60 cM)] of BHT post-treatment. In MCA carcinogenesis, QTL that included the H-2 locus (Chr 17, 18.431 cM; this range covered both MCA and MCA/BHT protocols) mandated tumor formation. Another MCA-generated QTL, at Chr 18 (3741 cM), was observed only in the presence of BHT. No susceptibility QTL was shared by the U and MCA carcinogenesis protocols.
Linkage analysis of susceptibility to BHT-induced pulmonary inflammation among the CXB RI strains
One QTL, at Chr 3 (76.287.6 cM), modulated sensitivity to more than one inflammatory response to BHT, specifically BAL protein concentration and macrophage infiltration (Table II
). Other QTL determining the extent of inflammation include Chr 9 (61 cM), Chr 15 (21.1 cM) and Chr 18 (37 cM) for BAL macrophages; Chr 3 (2225 cM) and Chr 4 (7.512.1 cM) for BAL lymphocytes; and Chr 8 (4345 cM), Chr 10 (6065 cM) and Chr 15 (46.761.7 cM) for COX-2 induction. Comparison of Tables I and II
reveals two QTL that affect susceptibility to both inflammation and carcinogenesis. These are Chr 15 (39.161.7 cM), which modifies both COX-2 induction and U and U/BHT carcinogenesis, and Chr 18 (3741 cM), which modulates both BAL macrophage infiltration and MCA/BHT two-stage carcinogenesis. Although the amount of COX-1 induced by BHT varied among CXB strains, no linkage that fit within the statistical criteria described in the Materials and methods was discerned, most likely due to lack of statistical power and/or small effect QTL.
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Discussion
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Susceptibility to lung carcinogenesis
Mapping studies to identify genes that regulate the predisposition to lung tumor development in mice have commonly used a single injection of U to induce tumors in the absence of additional co-carcinogens or promoting agents; a list of strains used for these analyses is given in Malkinson (10). It is reasonable that different carcinogenesis protocols would enlist contributions from unique genes, as pathways for metabolic activation and phase II detoxification of different chemical classes of each carcinogen are distinct. Molecular targets can also differ, as will the relative sensitivities of particular DNA adducts for repair. For example, the ultimate carcinogenic metabolite of U is a vinyl carbamate diol epoxide whose synthesis requires CYP 2E1 catalysis (25); whereas the polycyclic aromatic hydrocarbon, MCA, is metabolized by CYP IA1 (26). Whereas Kras is the probable initiating mutational site for both U (27) and MCA (28), U causes codon 61 mutations whereas MCA causes codon 12 mutations (29). Thus, it is interesting to compare QTL assignments for genes that govern the susceptibilities to lung tumor induction by U and MCA within a single set of inbred strains, and to determine whether addition of the BHT promoting agent to each carcinogenesis protocol uncovers additional modifier genes.
The susceptibility sites for MCA carcinogenesis observed herein were reported previously for U carcinogenesis; these are the H-2 region on Chr 17 (30,31) and the Chr 18 (3741 cM) site (3234). H-2 contains the major histocompatibility complex and genes encoding inflammatory cytokines, such as tumor necrosis factor
. Studies confirming that Pas2 resides within the H-2 region used congenic mice in which the H-2 haplotype of sensitive A/J mice was bred onto the background of the resistant B6 genome, and vice versa (35,36). The A/J H-2 haplotype increased the frequency of both chemically induced lung tumors and spontaneously arising tumors in B6 mice, and the B6 H-2 haplotype reduced lung tumor development in A/J mice.
Two unique susceptibility QTL in Table I
not reported previously to affect lung tumor development are on Chr 14 (43 cM) for U induction and on Chr 15 (39.155.6 cM) for both U and U/BHT carcinogenesis. New susceptibility genes may appear in mapping studies using different genetic backgrounds because genegene interactions are revealed by strain-dependent modifier alleles. Ours is the first QTL study of lung tumor susceptibility using the CXB RI strains derived from intermediate BALB and resistant B6 mice. As opposed to sensitive strains such as A/J where all mice treated with U develop many tumors, BALB mice have an intermediate susceptibility displaying a high lung tumor incidence (number of mice that develop tumors) but a low tumor multiplicity (number of tumors per mouse; 3234,37). Karasaki et al. (33) used BALB and resistant C3H mice in QTL analyses of lung tumor predisposition.
Nevertheless, using only 13 RI strains for genetic analysis necessitates that these QTL assignments be considered as provisional until independently confirmed. An illustration of the limitations of employing a small number of strains for mapping polygenic traits is our inability to detect the major Pas1 locus on Chr 6 as a genetic determinant. BALB mice have the sensitive Kras allele (38) that consists of a single copy of a 37 bp oligonucleotide stretch within intron 2 (39) and accounts for two-thirds of the variance between sensitive and resistant strains (30). The B6 progenitor contains the Kras allele associated with resistance to lung tumor development, namely, two copies of this 37 bp region (31,39). Of the 13 CXB RI strains, 12 had U-induced lung tumor multiplicities predicted by their Kras allele (15,38,40), i.e., those with the BALB allele developed tumors and those with the B6 allele did not. However, CXB 13 mice have the BALB Kras allele but are quite resistant to lung tumorigenesis. QTL analysis of F2 mice from a BALBxCXB13 cross, revealed a tumor suppressor allele in CXB 13 mice that overrides the contribution of the sensitive Kras allele (40). Thus, non-adherence of only one of these 13 CXB RI strains to the sensitive versus resistant Kras paradigm prevented detection of the Chr 6 QTL.
Susceptibility to BHT-induced pulmonary inflammation
A QTL linked to multiple inflammatory phenotypes was found at Chr 3 (76.287.6 cM) for vulnerability to BHT-induced elevations in BAL protein and macrophage contents. Interestingly, the Chr 8 (4345 cM) and Chr 10 (6065 cM) sites that modulated COX-2 induction by BHT display the same strain distribution patterns, but were opposite from each other in the direction of their effect. An additional six QTL exhibited linkage to at least one marker of BHT-induced lung inflammation. These are on Chr 9 (61 cM), Chr 15 (21.1 cM) and Chr 18 (37 cM) for macrophage infiltration; Chr 3 (2225 cM) and Chr 4 (7.512.1 cM) for lymphocyte recruitment and Chr 15 (61.7 cM) for COX-2 induction. None of the QTL regulating the magnitude of COX-2 induction contains the COX-2 structural gene, which is on Chr 1 (41).
Two of these QTL regulate the propensity toward pulmonary inflammation in response to other agents. The Chr 3 (76.287.6 cM) site regulates sensitivity to ozone-induced hyper-permeability (42), and the Chr 15 (46.761.7 cM) QTL affected methacholine-induced airway reactivity (43). The Chr 18 (37 cM) locus has not been reported to modulate other pulmonary inflammatory responses, but is orthologous to the cytokine-rich gene cluster on human Chr 5q31.1-q33 that regulates susceptibility to asthma (44). It thus appears that the degree of inflammation caused by BHT is regulated by several genes, some common to those governing pulmonary inflammation in response to other agents in both mice and humans, and others that may be unique.
QTL common to both lung carcinogenesis and inflammation susceptibilties
Chr 15 (39.161.7 cM) and Chr 18 (3741 cM) affected responsiveness to both BHT-induced carcinogenesis and inflammation. The Chr 15 (39.155.6 cM) site has not been reported previously to influence tumorigenesis, whereas the Chr 18 (3741 cM) site contains Par2 (3234).
Two of the carcinogenesis QTL in Table I
map to sites occupied by genes that modify pulmonary inflammation in response to stimuli other than BHT. The H-2 region affects several inflammatory responses, including methacholine-induced airway reactivity (45), ozone-induced inflammation (16) and acute lung injury (46) and particle-induced immune dysfunction (47). The Chr 15 (39.155.6 cM) carcinogenesis site affects airway hyper-responsiveness to methacholine (43). Of the QTL that moderate BHT-induced inflammation, the Chr 9 (61 cM) and Chr 18 (37 cM) loci that regulate macrophage infiltration also govern susceptibility to single agent-induced lung carcinogenesis (30,3234). Moreover, the Chr 4, Chr 9, Chr 17 and Chr 18 sites all correspond to frequently deleted orthologous sites in human lung cancer (10). This supports the validity of trying to identify these tumor modifier genes; their expression is altered during human lung neoplastic development and their identification portends translational applications. For example, lung adenocarcinoma patients in Japan had a propensity towards a particular KRAS polymorphism on Chr 12p (48), and the motivation for this investigation was that this human site is orthologous to mouse Kras.
The QTL intervals listed in Tables I and II
are up to 16 cM in size and encompass hundreds of genes. This interval size houses 1/100 of the genome and modulation of two different disease traits could map there by random chance, which is why Lander and Krugyak (24) recommend stringent statistical criteria to try to exclude this possibility. In spite of its poor resolution, the value of QTL mapping lies in predicting which human genes modify carcinogenesis, and genetic analysis using inbred mice is much easier than in the more highly variable human population. Narrowing a large QTL down to a specific gene candidate with assurance is difficult (49,50), but additional genetic analysis to refine the location of the genes regulating pulmonary inflammation and promotion susceptibilities, and thus identify them, is underway.
Co-localization of susceptibility QTL common to inflammation and cancer suggests that a gene at that locus moderates both inflammation and cancer susceptibility because this gene regulates inflammation, which, in turn, enhances tumorigenesis. Equally plausible, a single gene could regulate each pathology independently, without the inflammatory process per se affecting tumor growth. Our bias, bolstered by the potency and diverse biological activities of inflammatory mediators and the efficacy of chemoprevention by anti-inflammatory interventions (1215), is that inflammatory mediators modify tumor growth. Indeed, the extent of lymphocyte infiltration into mouse lung tumors has been quantified and correlated with tumor growth rate (51). Promoting agents enhance tumor growth when applied at any time following application of the initiating agent (52). Multiple stages of lung cancer pathogenesis may be enhanced by inflammatory mediators. The correspondence of QTL that regulate susceptibility to both pulmonary inflammation and carcinogenesis supports pre-clinical and clinical trials using non-toxic anti-inflammatory drugs for prevention, an approach that would be strengthened if combined with anti-neoplastic agents that have different mechanisms of action (53).
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Notes
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3 To whom correspondence should be addressed Email: al.malkinson{at}uchsc.edu 
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Acknowledgments
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We thank Drs Lori Dwyer-Nield, Lori Kisley, Steve Kleeberger, David Thompson and Jeanne Wehner for their helpful comments on this manuscript. This work was supported by USPHS grant CA33497.
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Received September 18, 2001;
revised December 20, 2001;
accepted December 21, 2001.