Abstract 4446: The allelic variants of Dock9 contribute to urethane-induced lung tumor susceptibility (2014)

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&amp;lt;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 &amp;lt;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