Identification of fat4 and tsc22d1 as novel candidate genes for spontaneous pulmonary adenomas.

Genetic influences that underlie spontaneous lung oncogenesis are poorly understood. The objective of this study was to determine the genetic influences on spontaneous pulmonary adenoma frequency and severity in 28 strains of mice as part of a large-scale aging study conducted at the Jackson Aging Center (http://agingmice.jax.org/). Genome-wide association studies were conducted in these strains with both low-density (132,000) and high-density (4,000,000) panel of single-nucleotide polymorphisms (SNP). Our analysis revealed that adenomas were relatively less frequent and less severe in females than males, and that loci implicated in frequency and severity were often different between male and female mice. While some of the significant loci identified mapped to genomic locations known to be responsible for carcinogen-induced cancers (e.g., Pas1), others were unique to our study. In particular, Fat4 was influential in males and Tsc22d1 was influential in females. SNPs implicated were predicted to alter amino acid sequence and change protein function. In summary, our results suggested that genetic influences that underlie pulmonary adenoma frequency are dependent on gender, and that Fat4 and Tsc22d1 are likely candidate genes to influence formation of spontaneous pulmonary adenoma in aging male and female mice, respectively.

[1]  Christopher P Austin,et al.  The Knockout Mouse Project , 2004, Nature Genetics.

[2]  Ron Korstanje,et al.  Genetic analysis of albuminuria in aging mice and concordance with loci for human diabetic nephropathy found in a genome-wide association scan. , 2010, Kidney international.

[3]  G. Long,et al.  Incidence of Spontaneous Neoplastic and Nonneoplastic Lesions in Charles River CD-1® Mice Varies with Breeding Origin , 1993, Toxicologic pathology.

[4]  Chao Qi,et al.  Identification of Fat4 as a candidate tumor suppressor gene in breast cancers , 2009, International journal of cancer.

[5]  A. González-Neira,et al.  Mouse Genome-Wide Association Mapping Needs Linkage Analysis to Avoid False-Positive Loci , 2009, PLoS genetics.

[6]  Ulrich Mohr,et al.  Pathobiology of the aging mouse , 1996 .

[7]  Stephen S. Hecht,et al.  Tobacco carcinogens, their biomarkers and tobacco-induced cancer , 2003, Nature Reviews Cancer.

[8]  S. Rehm,et al.  Influence of food restriction and body fat on life span and tumour incidence in female outbred Han:NMRI mice and two sublines. , 1985, Zeitschrift fur Versuchstierkunde.

[9]  Janan T. Eppig,et al.  The Mouse Tumor Biology database , 2008, Nature Reviews Cancer.

[10]  Michael Gruenberger,et al.  Pathbase: a database of mutant mouse pathology , 2004, Nucleic Acids Res..

[11]  M. Heller,et al.  Differential expression of TGFβ‐stimulated clone 22 in normal prostate and prostate cancer , 2006 .

[12]  A. Malkinson,et al.  At least four genes and sex are associated with susceptibility to urethane-induced pulmonary adenomas in mice. , 1994, Genetical research.

[13]  Gary A. Churchill,et al.  CGDSNPdb: a database resource for error-checked and imputed mouse SNPs , 2010, Database J. Biol. Databases Curation.

[14]  Yueming Ding,et al.  An efficient SNP system for mouse genome scanning and elucidating strain relationships. , 2004, Genome research.

[15]  M. Heller,et al.  Differential expression of TGFbeta-stimulated clone 22 in normal prostate and prostate cancer. , 2006, International journal of cancer.

[16]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[17]  T. Fujimori,et al.  Expression and cellular localization of TSC-22 in normal salivary glands and salivary gland tumors: implications for tumor cell differentiation. , 2008, Oncology reports.

[18]  Michael Gruenberger,et al.  Pathbase: a new reference resource and database for laboratory mouse pathology. , 2004, Radiation protection dosimetry.

[19]  R. Cardiff,et al.  Classification of Proliferative Pulmonary Lesions of the Mouse , 2004, Cancer Research.

[20]  R. Maronpot,et al.  Assignment of a locus for mouse lung tumor susceptibility to proximal Chromosome 19 , 1994, Mammalian Genome.

[21]  Steven Henikoff,et al.  SIFT: predicting amino acid changes that affect protein function , 2003, Nucleic Acids Res..

[22]  C. Bult,et al.  Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels , 2009, Aging cell.

[23]  J. Sundberg,et al.  The mouse as a model for understanding chronic diseases of aging: the histopathologic basis of aging in inbred mice , 2011, Pathobiology of aging & age related diseases.

[24]  S. Ohta,et al.  Molecular cloning and characterization of a transcription factor for the C-type natriuretic peptide gene promoter. , 1996, European journal of biochemistry.

[25]  Mark W. Moore,et al.  Pathology of the Laboratory Mouse , 2011, Toxicologic pathology.

[26]  J. Sundberg,et al.  Integrating mouse anatomy and pathology ontologies into a phenotyping database: Tools for data capture and training , 2008, Mammalian Genome.

[27]  D. Hémon,et al.  Lung Cancer Attributable to Indoor Radon Exposure in France: Impact of the Risk Models and Uncertainty Analysis , 2006, Environmental health perspectives.

[28]  Drinkwater Nr,et al.  Genetic Control of Carcinogenesis in Experimental Animals , 1991 .

[29]  J. Foekens,et al.  TSC22D1 and PSAP predict clinical outcome of tamoxifen treatment in patients with recurrent breast cancer , 2008, Breast Cancer Research and Treatment.

[30]  Howard L McLeod,et al.  Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice. , 2006, Cancer research.

[31]  J. R. Scotti,et al.  Available From , 1973 .

[32]  Mohammad Fallahi,et al.  An Integrated in Silico Gene Mapping Strategy in Inbred Mice , 2007, Genetics.

[33]  S. Badve,et al.  Estrogen promotes tumor progression in a genetically defined mouse model of lung adenocarcinoma. , 2008, Endocrine-related cancer.

[34]  Pengyuan Liu,et al.  Candidate lung tumor susceptibility genes identified through whole-genome association analyses in inbred mice , 2006, Nature Genetics.

[35]  J. Sundberg,et al.  A Data-capture Tool for Mouse Pathology Phenotyping , 2009, Veterinary pathology.

[36]  K. Svenson,et al.  Genetic influence on electrocardiogram time intervals and heart rate in aging mice. , 2009, American journal of physiology. Heart and circulatory physiology.

[37]  Gary A. Churchill,et al.  An imputed genotype resource for the laboratory mouse , 2008, Mammalian Genome.

[38]  M. You,et al.  Five loci, SLT1 to SLT5, controlling the susceptibility to spontaneously occurring lung cancer in mice. , 2005, Cancer research.

[39]  A. Malkinson.  The genetic basis of susceptibility to lung tumors in mice. , 1989, Toxicology.

[40]  N. Drinkwater,et al.  Genetic control of carcinogenesis in experimental animals. , 1991, Progress in experimental tumor research.

[41]  J. Kurie,et al.  A genetic mouse model for metastatic lung cancer with gender differences in survival , 2007, Oncogene.

[42]  G. Sheu,et al.  The association of human papillomavirus 16/18 infection with lung cancer among nonsmoking Taiwanese women. , 2001, Cancer research.

[43]  H. Fan,et al.  Retrovirus-induced ovine pulmonary adenocarcinoma, an animal model for lung cancer. , 2001, Journal of the National Cancer Institute.

[44]  D. Heckerman,et al.  Efficient Control of Population Structure in Model Organism Association Mapping , 2008, Genetics.

[45]  Carol J. Bult,et al.  Mouse Phenome Database , 2013, Nucleic Acids Res..