Lung Tumor Susceptibility Research Articles

Mapping of novel loci involved in lung and colon tumor susceptibility by the use of genetically selected mouse strains

Two non-inbred mouse lines, phenotypically selected for maximal (AIRmin) and minimal (AIRmax) acute inflammatory response, show differential susceptibility/resistance to the development of several chemically-induced tumor types. An intercross pedigree of these mice was generated and treated with the chemical carcinogen dimethylhydrazine, which induces lung and intestinal tumors. Genome wide high-density genotyping with the Restriction Site-Associated DNA genotyping (2B-RAD) technique was used to map genetic loci modulating individual genetic susceptibility to both lung and intestinal cancer. Our results evidence new common quantitative trait loci (QTL) for those phenotypes and provide an improved understanding of the relationship between genomic variation and individual genetic predisposition to tumorigenesis in different organs.

Abstract A1-20: Genetic control of Kras mutation specificity in mice

Abstract The selection and specificity of mutations occurring in genes that drive cancer is a highly complex process that remains poorly understood for even the most well studied oncogenes. The specific pattern of RAS mutations across different cancers is thought to be modulated by differences in carcinogen exposure and metabolism, local DNA features and repair mechanisms, tissue-specific expression patterns and functional differences of the RAS isoforms1. Less is known about functional differences between the various activating mutations in RAS that may lead to selection of particular mutants in mouse or human cancers. Studies of mouse cancer models have provided evidence for strong genetic background effects on allele-specificity of Ras mutations2 as well as on selection of particular mutations at Kras codon 61 in lung adenomas3. We have also recently demonstrated a major role of germline Kras status in mutation selection during initiation, where carcinogen-induced lung tumors from Kras WT mice carry mostly (94%) Q61R Kras mutations, while those from Kras heterozygous mice carry mostly (92%) Q61L mutations4. These data support the possibility that mutation specificity at Kras is influenced by genetic factors that may modulate, in trans, the levels or activity of Kras. In order to elucidate the genetic underpinnings of Kras mutation specificity, we characterized Kras mutations in carcinogen-induced lung tumors from a population of nearly 300 M. Musculus x M. Spretus backcrossed mice and performed genome-wide quantitative trait locus (QTL) mapping. Kras mutations occurred with complete specificity on the allele inherited from the susceptible strain, in agreement with previous observations. In addition, QTL mapping of lung cancer susceptibility was performed, and no Kras QTL was identified, in contrast to previous data obtained using other strains and breeding strategies. These approaches provide a framework for understanding the interactions between germline and somatic events that control Ras mutation specificity in cancer.

Abstract LB-134: A novel model to investigate Kras mutation specificity in the skin

Abstract The selection and specificity of mutations occurring in genes that drive cancer is a highly complex process that remains poorly understood for even the most well studied oncogenes. The specific pattern of RAS mutations across different cancers is thought to be modulated by differences in carcinogen exposure and metabolism, local DNA features and repair mechanisms, tissue-specific expression patterns and functional differences of the RAS isoforms1. Less is known about functional differences between the various activating mutations in RAS that may lead to selection of particular mutants in mouse or human cancers. Studies of mouse cancer models have provided evidence for strong genetic background effects on allele-specificity of Ras mutations2 as well as on selection of particular mutations at Kras codon 61 in lung adenomas3. We have also recently demonstrated a major role of germline Kras status in mutation selection during initiation, where carcinogen-induced lung tumors from Kras WT mice carry mostly (94%) Q61R Kras mutations, while those from Kras heterozygous mice carry mostly (92%) Q61L mutations4. In a M. Musculus (Mm) x M. Spretus (Ms) backcrossed population of HrasKO mice treated with DMBA/TPA, a model of Kras-driven tumorigenesis in the skin, we observed a wide spectrum of Kras mutations. Interestingly, genotype at the Kras locus significantly influenced Kras mutation specificity, with a switch from predominantly G13R mutations in Mm/Mm carcinomas to G12 and Q61L mutations in Mm/Ms carcinomas. Importantly, total Kras expression driven by the Mm Kras allele is higher than that driven by the Ms allele in the skin, and Kras mutations occur with high specificity for the Mm allele, suggesting that Q61L and G12 mutations may be suppressed by higher expression of the WT Kras allele in Kras Mm/Mm animals. We hypothesize that the ability of WT Kras to suppress certain mutants may be dependent on upstream activation by EGFR, and that this phenomenon may underlie the divergent responses to EGFR inhibition of colorectal cancer patients harboring Kras G12 versus G13 mutations5. Experiments to test this in mice by extended EGFR inhibition following carcinogen treatment are ongoing.

Abstract 4446: The allelic variants of Dock9 contribute to urethane-induced lung tumor susceptibility

Abstract Mouse lung tumors have histological and molecular features similar to human lung adenocarcinomas. Several lung tumor susceptibility loci have been identified through genome-wide association analysis in laboratory inbred mice. In this study, we employed a powerful strategy for association mapping that combines classic inbred strains for mapping resolution and additional recombinant inbred strains for enhanced mapping power. We performed a whole-genome association analysis for urethane-induced lung tumor multiplicity with 211,768 SNPs from 21 laboratory inbred mouse strains and 35 recombinant inbred strains (19 A×B and 16 B×A, derived from susceptible strain A/J and resistant strain C57BL/6J) and identified two genomic regions, each having at least one SNP strongly associated with urethane-induced lung tumor susceptibility (P<10-5). The most significant one (-log(P) = 6.8) co-localized with a major and previously identified locus of mouse Pulmonary Adenoma Susceptibility (Pas1) on the distal region of chromosome 6 and was refined to a region of <0.5 Mb in which at least two genes Kras2 and Casc1 are strong candidates. The second region we identified is on distal mouse chromosome 14. This locus spans about 700 kb (121.45-122.15 Mb) and includes four candidate genes including Farp1, Slk24, Slc15a1 and Dock9. The marker rs30937139 shows the strongest evidence of association is located within Dock9 (P = 3.94 × 10-6). Analysis of the genome sequences of 17 common mouse strains revealed that Dock9 carries a non-synonymous SNP in codon 1610 and this corresponds to a non-synomous change of arginine (CGG) in tumor susceptible strains, to Proline (CCG) in tumor resistant strains. The non-synonymous SNP that is significantly associated with the risk of lung cancer at codon 1610 (encoding a proline) is highly conserved across 20 different species. All tumor resistant mouse strains (such as C57BL/6J and 129S1/SvImJ) take the Dock9-resistance allele, ie. proline at codon 1610, while all the tumor susceptible strains (such as A/J and BALB/cByJ) take the Dock9 susceptible allele, i.e arginine at codon 1610. It suggests that 1610R SNP is a causal genetic variant that confers increased lung cancer risk. Tissue microarrays of 70 lung adenocarcinoma patients were done to examine DOCK9 expression in normal and tumor tissues by immunohistochemistry. Higher expression in tumor tissues than that in their matched normal tissues was identified in 53/58 (91.4%) patients (P=2.4×10-12). DOCK9 was localized mainly to epithelial tumor cells, but not normal epithelial cells. GST-CRIB (Cdc42 binding domain of PAK) pulldown assay showed that Dock9-1610P reduce GEF activity for Cdc42 compared to Dock9-1610R. These data suggest that Dock9 allelic variants may influence urethane-induced lung tumor susceptibility and play a tumorigenic role in lung cancer through activation of Cdc42. Citation Format: Yan Lu, Pengyuan Liu, Haris Vikis. The allelic variants of Dock9 contribute to urethane-induced lung tumor susceptibility. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4446. doi:10.1158/1538-7445.AM2014-4446

Mouse pulmonary adenoma susceptibility 1 locus is an expression QTL modulating Kras-4A.

Pulmonary adenoma susceptibility 1 (Pas1) is the major locus responsible for lung tumor susceptibility in mice; among the six genes mapping in this locus, Kras is considered the best candidate for Pas1 function although how it determines tumor susceptibility remains unknown. In an (A/J×C57BL/6)F4 intercross population treated with urethane to induce lung tumors, Pas1 not only modulated tumor susceptibility (LOD score = 48, 69% of phenotypic variance explained) but also acted, in lung tumor tissue, as an expression quantitative trait locus (QTL) for Kras-4A, one of two alternatively spliced Kras transcripts, but not Kras-4B. Additionally, Kras-4A showed differential allelic expression in lung tumor tissue of (A/J×C57BL/6)F4 heterozygous mice, with significantly higher expression from the A/J-derived allele; these results suggest that cis-acting elements control Kras-4A expression. In normal lung tissue from untreated mice of the same cross, Kras-4A levels were also highly linked to the Pas1 locus (LOD score = 23.2, 62% of phenotypic variance explained) and preferentially generated from the A/J-derived allele, indicating that Pas1 is an expression QTL in normal lung tissue as well. Overall, the present findings shed new light on the genetic mechanism by which Pas1 modulates the susceptibility to lung tumorigenesis, through the fine control of Kras isoform levels.

The error-prone DNA polymerase ι provides quantitative resistance to lung tumorigenesis and mutagenesis in mice

Opposite undamaged nucleotide T, DNA polymerase ι (Polι) preferentially incorporates G rather than A, violating the Watson-Crick rule. Although the actual biological role of Polι remains enigmatic, we have identified its coding gene as a candidate for pulmonary adenoma resistance 2 (Par2), a mouse quantitative trait locus modulating chemically induced lung tumor susceptibility. Notably, the most tumor-sensitive Par2 allele possessed by the 129X1/SvJ mouse is associated with a loss-of-function mutation in Polι. To determine whether the nonfunctional Polι is responsible for the 129X1/SvJ-specific Par2 phenotype, we knocked out Polι in a C57BL/6J mouse carrying a less tumor-sensitive Par2 allele. Disruption of the C57BL/6J Polι conferred 129X1/SvJ-like sensitivity on the C57BL/6J Par2 locus and increased the in vivo mutation frequency in the lung, providing definitive proof that Polι causes the Par2 effect and inhibits tumorigenesis and mutagenesis, despite its extreme replication infidelity.

Response of the mouse lung transcriptome to welding fume: effects of stainless and mild steel fumes on lung gene expression in A/J and C57BL/6J mice

BackgroundDebate exists as to whether welding fume is carcinogenic, but epidemiological evidence suggests that welders are an at risk population for the development of lung cancer. Recently, we found that exposure to welding fume caused an acutely greater and prolonged lung inflammatory response in lung tumor susceptible A/J versus resistant C57BL/6J (B6) mice and a trend for increased tumor incidence after stainless steel (SS) fume exposure. Here, our objective was to examine potential strain-dependent differences in the regulation and resolution of the lung inflammatory response induced by carcinogenic (Cr and Ni abundant) or non-carcinogenic (iron abundant) metal-containing welding fumes at the transcriptome level.MethodsMice were exposed four times by pharyngeal aspiration to 5 mg/kg iron abundant gas metal arc-mild steel (GMA-MS), Cr and Ni abundant GMA-SS fume or vehicle and were euthanized 4 and 16 weeks after the last exposure. Whole lung microarray using Illumina Mouse Ref-8 expression beadchips was done.ResultsOverall, we found that tumor susceptibility was associated with a more marked transcriptional response to both GMA-MS and -SS welding fumes. Also, Ingenuity Pathway Analysis revealed that gene regulation and expression in the top molecular networks differed between the strains at both time points post-exposure. Interestingly, a common finding between the strains was that GMA-MS fume exposure altered behavioral gene networks. In contrast, GMA-SS fume exposure chronically upregulated chemotactic and immunomodulatory genes such as CCL3, CCL4, CXCL2, and MMP12 in the A/J strain. In the GMA-SS-exposed B6 mouse, genes that initially downregulated cellular movement, hematological system development/function and immune response were involved at both time points post-exposure. However, at 16 weeks, a transcriptional switch to an upregulation for neutrophil chemotactic genes was found and included genes such as S100A8, S100A9 and MMP9.ConclusionsCollectively, our results demonstrate that lung tumor susceptibility may predispose the A/J strain to a prolonged dysregulation of immunomodulatory genes, thereby delaying the recovery from welding fume-induced lung inflammation. Additionally, our results provide unique insight into strain- and welding fume-dependent genetic factors involved in the lung response to welding fume.

Transcriptome of normal lung distinguishes mouse lines with different susceptibility to inflammation and to lung tumorigenesis

AIRmax and AIRmin mouse lines show a differential lung inflammatory response and differential lung tumor susceptibility after urethane treatment. The transcript profile of ∼24,000 known genes was analyzed in normal lung tissue of untreated and urethane-treated AIRmax and AIRmin mice. In lungs of untreated mice, inflammation-associated genes involved in pathways such as “leukocyte transendothelial migration”, “cell adhesion” and “tight junctions” were differentially expressed. Moreover, gene expression levels differed significantly in urethane-treated mice; in AIRmin mice, modulation of expression of genes involved in pathways associated with inflammatory response paralleled the previously observed persistent infiltration of inflammatory cells in the lung of these mice.

Genetic variants cis-regulating Xrn2 expression contribute to the risk of spontaneous lung tumor

Gene expression variation is an important mechanism underlying susceptibility to complex disease. In comparison with tobacco-related lung carcinogenesis, lung cancer in nonsmokers may involve important and etiologically distinct causal pathways. In this study, we conducted a genome-wide association study on spontaneous lung tumor incidence in inbred mice and identified a major susceptibility locus on mouse chromosome 2 (rs27328255, P=6.68 x 10(-7)). We then evaluated the correlations of polymorphisms with the transcription of positional candidate genes in normal lungs. Single-nucleotide polymorphism rs27328255 was consistently and strongly associated (P=7.42 x 10(-9)) in cis with transcript levels of Xrn2. We further showed that Xrn2 promotes proliferation and inhibits squamous differentiation in human lung epithelial cells and polymorphisms in human homolog XRN2 are associated with human lung cancer (rs2025811, P=1.90 x 10(-3), OR=1.20). We conclude that genetic variants regulating Xrn2 expression in cis are determinants of spontaneous lung tumor susceptibility in mice and have genetic equivalents in lung cancer susceptibility in human beings. Identifying Xrn2 as a major candidate for spontaneous lung cancer has important implications for the diagnosis and treatment of lung cancer as well as delineation of the mechanisms underlying the genesis of lung cancer in nonsmokers.

Identification of Las2, a Major Modifier Gene Affecting the Pas1 Mouse Lung Tumor Susceptibility Locus

Lung cancer is the leading cause of cancer death worldwide. Here, we describe a genome-wide association study of chemically induced lung tumorigenesis on 593 mice from 21 inbred strains using 115,904 genotyped and 1,952,918 imputed single nucleotide polymorphisms (SNPs). Using a genetic background-controlled genome search, we identified a novel lung tumor susceptibility gene Las2 (Lung adenoma susceptibility 2) on distal chromosome 18. Las2 showed strong association with resistance to tumor induction (rs30245983; P = 1.87 x 10(-9)) as well as epistatic interactions (P = 1.71 x 10(-3)) with the pulmonary adenoma susceptibility 1 locus, a major locus affecting mouse lung tumor development (rs13459098, P = 5.64 x 10(-27)). Sequencing analysis revealed four nonsynonymous SNPs and two insertions/deletions in the susceptible allele of Las2, resulting in the loss of tumor suppressor activities in both cell colony formation and nude mouse tumorigenicity assays. Deletion of LAS2 was observed in approximately 40% of human lung adenocarcinomas, implying that loss of function of LAS2 may be a key step for lung tumorigenesis.

Mouse Genome-Wide Association Mapping Needs Linkage Analysis to Avoid False-Positive Loci

We carried out genome-wide association (GWA) studies in inbred mouse strains characterized for their lung tumor susceptibility phenotypes (spontaneous or urethane-induced) with panels of 12,959 (13K) or 138,793 (140K) single-nucleotide polymorphisms (SNPs). Above the statistical thresholds, we detected only SNP rs3681853 on Chromosome 5, two SNPs in the pulmonary adenoma susceptibility 1 (Pas1) locus, and SNP rs4174648 on Chromosome 16 for spontaneous tumor incidence, urethane-induced tumor incidence, and urethane-induced tumor multiplicity, respectively, with the 13K SNP panel, but only the Pas1 locus with the 140K SNP panel. Haplotype analysis carried out in the latter panel detected four additional loci. Loci reported in previous GWA studies failed to replicate. Genome-wide genetic linkage analysis in urethane-treated (BALB/c×C3H/He)F2, (BALB/c×SWR/J)F2, and (A/J×C3H/He)F2 mice showed that Pas1, but none of the other loci detected previously or herein by GWA, had a significant effect. The Lasc1 gene, identified by GWA as a functional element (Nat. Genet., 38:888–95, 2006), showed no genetic effects in the two independent intercross mouse populations containing both alleles, nor was it expressed in mouse normal lung or lung tumors. Our results indicate that GWA studies in mouse inbred strains can suffer a high rate of false-positive results and that such an approach should be used in conjunction with classical linkage mapping in genetic crosses.

The Kras2 oncogene and mouse lung carcinogenesis

Activating point mutations of the mouse Kras2 oncogene or its human homologue, KRAS, are critical for lung adenocarcinoma genesis, independent of the species. Significantly, in the mouse, several polymorphic Kras2 alleles have been identified, which cosegregate with genetic susceptibility to chemical induction of lung tumors. Moreover, a major lung tumor susceptibility locus, the Pas1 (Pulmonary adenoma susceptibility 1), was found to colocalize with Kras2 on distal chromosome 6 on linkage analysis. The Kras2 may thus be involved in both cellular transformation and genetic control of tumor susceptibility. In this review, the focus is on current knowledge regarding the relationship between Kras2 and experimental mouse lung carcinogenesis, especially from the aspect of disease predisposition. Because mouse and human lung tumors share considerable similarities, the experimental information should provide clues to personalized medicine in the human setting.

Candidate lung tumor susceptibility genes identified through whole-genome association analyses in inbred mice

We performed a whole-genome association analysis of lung tumor susceptibility using dense SNP maps ( approximately 1 SNP per 20 kb) in inbred mice. We reproduced the pulmonary adenoma susceptibility 1 (Pas1) locus identified in previous linkage studies and further narrowed this quantitative trait locus (QTL) to a region of less than 0.5 Mb in which at least two genes, Kras2 (Kirsten rat sarcoma oncogene 2) and Casc1 (cancer susceptibility candidate 1; also known as Las1), are strong candidates. Casc1 knockout mouse tumor bioassays showed that Casc1-deficient mice were susceptible to chemical induction of lung tumors. We also found three more genetic loci for lung adenoma development. Analysis of one of these candidate loci identified a previously uncharacterized gene Lasc1, bearing a nonsynonymous substitution (D102E). We found that the Lasc1 Glu102 allele preferentially promotes lung tumor cell growth. Our findings demonstrate the prospects for using dense SNP maps in laboratory mice to refine previous QTL regions and identify genetic determinants of complex traits.

A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice

Pulmonary adenoma susceptibility 1 (Pas1) is the major mouse lung cancer susceptibility locus on chromosome 6 (ref. 1). Kras2 is a common target of somatic mutation in chemically induced mouse lung tumors and is a candidate Pas1 gene. M. spretus mice (SPRET/Ei) carry a Pas1 resistance haplotype for chemically induced lung tumors. We demonstrate that the SPRET/Ei Pas1 allele is switched from resistance to susceptibility by fixation of the parental origin of the mutant Kras2 allele. This switch correlates with low expression of endogenous Kras2 in SPRET/Ei. We propose that the Pas1 modifier effect is due to Kras2, and that a sensitive balance between the expression levels of wild-type and mutant alleles determines lung tumor susceptibility. These data demonstrate that cancer predisposition should also be considered in the context of somatic events and could have major implications for the design of human association studies to identify cancer susceptibility genes.

A V141L polymorphism of the human LRMP gene is associated with survival of lung cancer patients

Mouse Lrmp and Casc1 genes are candidates for the pulmonary adenoma susceptibility 1 (Pas1) locus, the major determinant of strain variation in lung tumor susceptibility. These genes contain coding and non-coding single nucleotide polymorphisms (SNPs) strongly associated with lung tumor risk in mice. Analysis of LRMP and CASC1 gene SNPs in 361 lung adenocarcinoma (ADCA) patients and 327 healthy controls revealed common SNPs in LRMP (V141L and S197C) and CASC1 (R33S and three intronic variations), and none showed a significant association with lung ADCA risk. However, in the time-dependent Cox regression model, after adjustment for age, gender, smoking history and clinical stage, the carrier status of the Leu variation (V141L) of the LRMP gene was associated with higher mortality in patients with age at tumor onset < or = 65 years [hazard ratio (HR) 2.3; 95% CI 1.4-3.7; P = 0.001]. These findings suggest that the LRMP V141L polymorphism can predict survival in lung ADCA and that the role of LRMP and CASC1 in human lung cancer risk may differ from that in mice.

Altered Tumor Biology and Tumorigenesis in Irradiated and Chemical Carcinogen-Treated Single and Combined Connexin32/p27Kip1-Deficient Mice

Connexin32 knockout mice (Cx32-KO) exhibit increased chemical and radiation-induced liver and lung tumorigenesis. This increased tumor incidence is associated with altered tumor biology including enhanced tumor progression and an increased percent of MAPK-active tumors. Likewise, mice lacking the tumor suppressor/cell cycle regulator p27Kip1 exhibit increased tumorigenesis in a variety of tissues following chemical and radiation induction. Interestingly, in a double-deficient mouse model (DKO), additional loss of p27Kip1 in a Cx32-KO background results in attenuation of liver and lung tumorigenesis as well as MAPK activation profiles, suggesting pathway interaction. While these mouse strains exhibit altered liver and lung tumor susceptibility following both chemical (DEN) and radiation (X-ray) induction protocols, comparisons of the resulting tumor incidence, multiplicity, tumor progression, and MAPK activation in response to these two distinct carcinogens underscores the separate influence of each individual gene on both tumor formation and activation of specific oncogenic pathways. Furthermore, these studies demonstrate that different carcinogens interact disparately with Cx32/p27Kip1 genotypic backgrounds in situ resulting in varied tumorigenic response.

IDENTIFICATION OF GENETIC POLYMORPHISMS THROUGH COMPARATIVE DNA SEQUENCE ANALYSIS ON THE K-ras GENE: IMPLICATIONS FOR LUNG TUMOR SUSCEPTIBILITY

In the present study, the authors performed a comparative DNA sequence analysis of the K-ras gene. By comparing sequences from different mouse inbred strains, the authors have identified new nucleotide polymorphisms in the noncoding regions of mouse K-ras gene. They have also identified noncoding DNA segments evolutionarily conserved among the human, mouse, and rat. Computational analysis for transcription factor binding sites suggests that these polymorphic and conserved DNA sequences harbor potential cis-regulatory elements, which may contribute to the transcriptional regulation of the K-ras gene. Further studies on these potential regulatory sites may help to elucidate the fundamental mechanism underlying allele-specific activation and expression of K-ras gene in hybrid mouse lung tumors, which determines lung tumor susceptibility in mice.

Novel loci controlling lymphocyte proliferative response to cytokines and their clustering with loci controlling autoimmune reactions, macrophage function and lung tumor susceptibility

Novel genotyping and statistical tools have led to mapping of numerous QTL loci for multigenic traits that previously could not be detected. The relationships of these QTL families to other QTL families and the functional specialization of their members can now be studied. We have mapped a number of loci controlling activation of T lymphocytes by mitogens and cytokines and their capacity to produce cytokines. In (O20xOcB-9)F2 hybrids, we mapped 3 novel loci controlling proliferative T-cell response to cytokines IL-2 and IL-4 (Cinda3) or IL-4 only (Cinda4 and Cinda5). OcB-9 allele at Cinda3 controls a higher response than the O20 allele to both IL-2 and IL-4, and OcB-9 alleles of Cinda4 and Cinda5 control higher response to IL-4. These novel Cinda loci and the previously mapped Cinda1 locus seem to be located in genomic regions together with other QTL families: macrophage function loci Marif1 and Marif2, proteoglycan-induced arthritis loci Pgia4, Pgia7 and Pgia12 and lung tumor susceptibility loci Sluc1, Sluc4, Sluc6 and Sluc20. The possible relevance of these QTL associations in several different sites of the genome for the immune response, inflammation and tumorigenesis has to be elucidated.

Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities.

Chronic inflammation predisposes toward many types of cancer. Chronic bronchitis and asthma, for example, heighten the risk of lung cancer. Exactly which inflammatory mediators (e.g., oxidant species and growth factors) and lung wound repair processes (e.g., proangiogenic factors) enhance pulmonary neoplastic development is not clear. One approach to uncover the most relevant biochemical and physiological pathways is to identify genes underlying susceptibilities to inflammation and to cancer development at the same anatomic site. Mice develop lung adenocarcinomas similar in histology, molecular characteristics, and histogenesis to this most common human lung cancer subtype. Over two dozen loci, called Pas or pulmonary adenoma susceptibility, Par or pulmonary adenoma resistance, and Sluc or susceptibility to lung cancer genes, regulate differential lung tumor susceptibility among inbred mouse strains as assigned by QTL (quantitative trait locus) mapping. Chromosomal sites that determine responsiveness to proinflammatory pneumotoxicants such as ozone (O3), particulates, and hyperoxia have also been mapped in mice. For example, susceptibility QTLs have been identified on chromosomes 17 and 11 for O3-induced inflammation (Inf1, Inf2), O3-induced acute lung injury (Aliq3, Aliq1), and sulfate-associated particulates. Sites within the human and mouse genomes for asthma and COPD phenotypes have also been delineated. It is of great interest that several susceptibility loci for mouse lung neoplasia also contain susceptibility genes for toxicant-induced lung injury and inflammation and are homologous to several human asthma loci. These QTLs are described herein, candidate genes are suggested within these sites, and experimental evidence that inflammation enhances lung tumor development is provided.

Evidence That Inflammation Encourages Pulmonary Adenocarcinoma Formation in Mice: Clinical Implications

Epidemiologic associations between inflammation and lung cancer include an increased cancer risk in COPD and asthma patients, familial clustering of pulmonary inflammatory diseases and lung cancer, and a decreased cancer incidence among long-term aspirin users. Experimental evidence that inflammation enhances the development of lung tumors in mice includes the following: chromosomal sites that determine susceptibilities to lung injury/inflammation in response to environmental toxins also regulate lung tumor susceptibility; reduced or raised tumorigenesis in mice that are null for, or that overexpress, enzymes that synthesize inflammatory mediators and their receptors; decreased tumor formation following the administration of antiinflammatory drugs such as budesonide and indomethacin; biochemical markers of inflammation such as the elevated expression of enzymes catalyzing eicosanoid biosynthesis and nitric oxide formation within and adjacent to tumor sites; and the incursion of activated inflammatory cells into and peripheral to the tumor mass.