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.
[Show abstract][Hide abstract] ABSTRACT: There are 15 different DNA polymerases encoded in mammalian genomes, which are specialized for replication, repair or the tolerance of DNA damage. New evidence is emerging for lesion-specific and tissue-specific functions of DNA polymerases. Many point mutations that occur in cancer cells arise from the error-generating activities of DNA polymerases. However, the ability of some of these enzymes to bypass DNA damage may actually defend against chromosome instability in cells, and at least one DNA polymerase, Pol ζ, is a suppressor of spontaneous tumorigenesis. Because DNA polymerases can help cancer cells tolerate DNA damage, some of these enzymes might be viable targets for therapeutic strategies.
Nature Reviews Cancer 02/2011; 11(2):96-110. DOI:10.1038/nrc2998 · 37.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
To identify genes which influence the fibrotic response to thoracic cavity radiotherapy, we combined a genome wide single nucleotide polymorphism (SNP) association evaluation of inbred strain response with prior linkage and gene expression data.
Material and methods:
Mice were exposed to 18Gy whole thorax irradiation and survival, bronchoalveolar cell differential, and histological alveolitis and fibrosis phenotypes were determined. Association analyses were completed with 1.8 million SNPs in single markers and haplotypes.
Nine strains developed significant fibrosis and 11 strains succumbed to alveolitis only or alveolitis with minimal fibrosis. Post irradiation survival time (p<0.001) and bronchoalveolar lavage neutrophil percent (p=0.055) were correlated with extent of alveolitis and were not significantly correlated with fibrosis. Genome wide SNP analysis identified 10 loci as significantly associated with radiation-induced fibrotic lung disease (p<8.41×10(-6); by permutation test), with the most significant SNP within a conserved non-coding region downstream of cell adhesion molecule 1 (Cadm1). Haplotype and SNP analyses performed within previously-identified loci revealed additional genes containing SNPs associated with fibrosis including Slamf6 and Cdkn1a.
Combining genomic approaches identified variation within specific genes which function in the tissue response to injury as associated with fibrosis following thoracic irradiation in mice.
Radiotherapy and Oncology 09/2012; 105(3). DOI:10.1016/j.radonc.2012.08.004 · 4.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary fibrosis is a disease of significant morbidity, with an incompletely defined genetic basis. Herein, we combine linkage and association studies to identify genetic variation associated with pulmonary fibrosis in mice. Mice were treated with bleomycin by osmotic minipump and pulmonary fibrosis was histologically assessed 6 weeks later. Fibrosis was mapped in C57BL6/J (fibrosis susceptible) x A/J (resistant) F2 mice, and the major identified linkage interval evaluated in consomic mice. Genome-wide and linkage interval genes were assessed for association to fibrosis using phenotypic data from 23 inbred strains and the mouse single nucleotide polymorphism map. Pulmonary fibrosis susceptibility mapped to a locus on chromosome 17, which was verified with consomic mice, and to three additional suggestive loci which may interact with alleles on chromosome 17 to affect the trait, in F2 mice. Two of the loci, including the region on chr 17, are homologous to previously mapped loci of human idiopathic fibrosis. Of the 23 phenotyped mouse strains four developed significant fibrosis and the majority presented minimal disease. Genome wide and linkage region specific association studies revealed 11 pulmonary expressed genes (including the autophagy gene Cep55 and Masp2, which is a complement component) to have polymorphisms significantly associated with bleomycin-induced fibrotic lung disease. In conclusion, genomic approaches were used to identify linkage intervals and specific genetic variation associated with pulmonary fibrosis in mice. The common loci and similarity in phenotype suggest these findings to be of relevance to clinical pulmonary fibrosis.
American Journal of Respiratory Cell and Molecular Biology 12/2012; 48(3). DOI:10.1165/rcmb.2012-0078OC · 3.99 Impact Factor
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