At Least Four Loci and Gender Are Associated with Susceptibility to the Chemical Induction of Lung Adenomas in A/J × BALB/c Mice

Festing, Michael F. W.; Lin, Liang; Devereux, Theodora R.; Gao, Feng; Yang, Aili; Anna, Colleen H.; White, Catherine M.; Malkinson, Alvin M.; You, Ming

doi:10.1006/geno.1998.5450

Cited by 64 publications

(49 citation statements)

References 23 publications

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“…We aligned these three sequences using the Clustalw software. 7 As shown in Fig. 5, the conserved amino acids are mainly clustered in NH 2 -terminal region consistent with the previous study (22).…”

Section: Expression and Nucleotide Polymorphism Analyses Of Genes In supporting

confidence: 90%

“…In (A/J ϫ BALB/c) F1 mice, the relatively resistant BALB/cJ phenotype was dominant over the high susceptibility of A/J mice (6). Additional analysis on F2 hybrids and backcross mice supported the hypothesis that a major locus named Par2 accounts for the difference in adenoma susceptibility between A/J mice and BALB/cJ mice (7). Par2 is mapped to the mouse chromosome 18 and accounts for 60% phenotype variance (7)(8)(9).…”

Section: Introductionmentioning

confidence: 89%

“…Additional analysis on F2 hybrids and backcross mice supported the hypothesis that a major locus named Par2 accounts for the difference in adenoma susceptibility between A/J mice and BALB/cJ mice (7). Par2 is mapped to the mouse chromosome 18 and accounts for 60% phenotype variance (7)(8)(9). The resistance of BALB/cJ mice appears due to the interaction between the Pas1 QTL and Par2 QTL in the BALB/cJ mouse genome (10).…”

Section: Introductionmentioning

confidence: 89%

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Pol ι Is a Candidate for the Mouse Pulmonary Adenoma Resistance 2 Locus, a Major Modifier of Chemically Induced Lung Neoplasia

Wang¹,

Devereux

Vikis

et al. 2004

Cancer Research

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In this study, we performed systematic candidate gene analyses of the Pulmonary adenoma resistance 2 locus. Differential gene expression in lung tissues and nucleotide polymorphisms in coding regions between A/J and BALB/cJ mice were examined using reverse transcription-PCR and direct sequencing. Although not all genes in the interval were analyzed at this moment due to the recent database updating, we have found that the Pol gene, encoding the DNA polymerase , contains 25 nucleotide polymorphisms in its coding region between A/J and BALB/cJ mice, resulting in a total of ten amino acid changes. Primer extension assays with purified BALB/cJ and A/J proteins in vitro demonstrate that both forms of Pol are active but that they may differ in substrate discrimination, which may affect the formation of Kras2 mutations in mouse lung tumors. Altered expression of POL protein and an amino acid-changing nucleotide polymorphism were observed in human lung cancer cells, suggesting a possible role in the development of lung cancer. Thus, our data support the Pol gene as a modifier of lung tumorigenesis by altering DNA polymerase activity.

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Section: Expression and Nucleotide Polymorphism Analyses Of Genes In supporting

confidence: 90%

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 89%

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Pol ι Is a Candidate for the Mouse Pulmonary Adenoma Resistance 2 Locus, a Major Modifier of Chemically Induced Lung Neoplasia

Wang¹,

Devereux

Vikis

et al. 2004

Cancer Research

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“…A single BALB Par2 allele was found to reduce mean tumor multiplicity by about 50%. Subsequently, the phenotypic e ect of BALB Par2 on chromosome 18 was con®rmed by other laboratories (Manenti et al, 1997;Festing et al, 1998;Zhang et al, 2000).…”

Section: Introductionmentioning

confidence: 78%

Fine chromosomal localization of the mouse Par2 gene that confers resistance against urethane-induction of pulmonary adenomas

2001

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BALB/cByJ mice are 14 times more resistant to urethaneinduction of pulmonary adenomas than the susceptible A/ J strain. Our previous linkage analysis of (A/J x BALB/ cByJ)F 1 x A/J backcross mice provided statistical evidence that a major resistance locus of BALB/cByJ with a dominant e ect, designated Par2 (Pulmonary adenoma resistance 2), exists within an approximately 25 cM section of distal chromosome 18. To facilitate molecular identi®cation of the Par2 locus, the present study was conducted to ®nely localize its chromosomal position utilizing Par2-congenic mice. Male BALB/cByJ mice were mated with female C57BL/6J mice carrying recessive Par2 alleles and their male F 1 progeny were backcrossed to female BALB/cByJ mice. A male backcross mouse heterozygous within the Par2 interval of 25 cM was randomly selected and again backcrossed to female BALB/cByJ mice. This backcross-selection cycle was simply repeated to produce semi-congenic mice with a general BALB/cByJ genetic background except for the Par2 interval, where the mice were heterozygous with paternal C57BL/6J alleles and maternal BALB/cByJ alleles. After the 6th or 7th backcross, nine male mice possessing a recombination within the paternal Par2 interval were retained and crossed to female A/J mice. Resultant progeny were treated with urethane and examined for lung tumor development in order to deduce the Par2 genotypes of the recombinants through linkage analysis. By comparing the deduced Par2 genotype of each recombinant with its recombinational breakpoint, the Par2 locus was con®ned to an approximately 0.5 cM region¯anked by D18Mit103 and D18Mit188 loci. Our results indicate that fully congenic mice conventionally established by at least nine simple backcrosses or by the speed congenic method are not necessarily required for ®ne mapping of quantitative trait loci. In the case of the Par2 locus, we found that semi-congenic mice after as few as four simple backcrosses were useful for this purpose. The map information obtained in this study should enable subsequent positional cloning of the Par2 gene. Oncogene (2001) 20, 3979 ± 3985.

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“…Two other nearby lung tumor susceptibility loci (M. on chromosome 6 might also contribute to lung tumor susceptibility. At least 12 other Pas loci have been mapped within the mouse genome (Obata et al 1996;Devereux and Kaplan 1998;Festing et al 1998;Malkinson 1999). Using recombinant congenic strains for multilocus fine mapping of F2 mice, 30 different loci conferring susceptibility to lung cancer (Sluc) were identified (Fijneman et al 1998;Tripodis et al 2001).…”

Section: Mouse Models For Spontaneous or Chemically Induced Lung Tumorsmentioning

confidence: 99%

Mouse models for human lung cancer

Meuwissen

Berns²

2005

Genes Dev.

271

243

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In recent years several new mouse models for lung cancer have been described. These include models for both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Tumorigenesis in these conditional mouse tumor models can be initiated in adult mice through Cre-recombinase-induced activation of oncogenic mutations in a subset of the cells. They present a marked improvement over mouse models that depend on carcinogen induction of tumors. These models permit us to study the consecutive steps involved in initiation and progression and allow us to address questions like the cell of origin, and the role of cancer stem cells in the maintenance of these tumors. They now need to be validated as suitable preclinical models for intervention studies in which questions with respect to therapy response and resistance can be addressed.During the last decades lung cancer has become the leading cause of cancer deaths in the world, accounting for even more solid tumor deaths than breast, pancreatic, prostate, and colorectal combined (Landis et al. 1999). More then 170,000 new cases are being diagnosed each year in the United States alone, of whom ∼160,000 will eventually die, representing 28% of all cancer deaths (Jemal et al. 2004). Worldwide more than a million deaths are due to lung cancer. Tobacco smoking is the major causal agent, being responsible for ∼85% of the lung cancer incidence. Other respiratory exposure to occupational or environmental carcinogens, such as asbestos or radon, and yet unknown genetic factors contribute to the remaining 15% . Although smoking cessation before the age of 30 does substantially reduce the risk of lung cancer, this is significantly less for those who stop smoking at 50 or 60 yr (Peto et al. 2000;Doll et al. 2004). Interestingly, nearly 50% of all first diagnosed lung cancers in the United States are from people who stopped smoking at least 5 or more years ago (Peto and Lopez 2001). This indicates that extensive damage to the respiratory tract can persist over many years. Indeed, recent studies (Mao 2002;Pfeifer et al. 2002;Wistuba et al. 2002) showed the presence of multiple genetic lesions, often manifested in clonal patches of cells in respiratory epithelium of current and former smokers.Lung cancer can be divided into two major histopathological groups: non-small-cell lung cancer (NSCLC) (Van Zandwijk et al. 1995) SCLC and NSCLC show major differences in histopathologic characteristics that can be explained by the distinct patterns of genetic lesions found in both tumor classes . Responsiveness to treatment with chemotherapy and/or radiation also differs significantly between NSCLC and SCLC and has a dramatic effect on clinical treatment outcome. The overall 5-yr survival rate for lung cancer is ∼14% (Travis et al. 1995); for SCLC alone it is even worse, ∼5% (Worden and Kalemkerian 2000).Spontaneous lung tumors in mice are similar in morphology, histopathology, and molecular characteristics to human adenocarcinomas. Mouse models for lung cancer can thus serve as a valua...

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At Least Four Loci and Gender Are Associated with Susceptibility to the Chemical Induction of Lung Adenomas in A/J × BALB/c Mice

Cited by 64 publications

References 23 publications

Pol ι Is a Candidate for the Mouse Pulmonary Adenoma Resistance 2 Locus, a Major Modifier of Chemically Induced Lung Neoplasia

Pol ι Is a Candidate for the Mouse Pulmonary Adenoma Resistance 2 Locus, a Major Modifier of Chemically Induced Lung Neoplasia

Fine chromosomal localization of the mouse Par2 gene that confers resistance against urethane-induction of pulmonary adenomas

Mouse models for human lung cancer

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