STANDARD_NAME JI_CARCINOGENESIS_BY_KRAS_AND_STK11_DN SYSTEMATIC_NAME M1767 COLLECTION C2:CGP MSIGDB_URL https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/JI_CARCINOGENESIS_BY_KRAS_AND_STK11_DN NAMESPACE MOUSE_GENE_SYMBOL DESCRIPTION_BRIEF Cluster B: genes down-regulated in primary lung tumors driven by KRAS [GeneID=3845] activation and loss of STK11 [GeneID=6794]; also up-regulated in human squamous cell carcinoma (SCC) vs adenocarcinoma subtype of NSCLC (non-small cell lung cancer). DESCRIPTION_FULL Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis. PMID 17676035 GEOID GSE6135 AUTHORS Ji H,Ramsey MR,Hayes DN,Fan C,McNamara K,Kozlowski P,Torrice C,Wu MC,Shimamura T,Perera SA,Liang MC,Cai D,Naumov GN,Bao L,Contreras CM,Li D,Chen L,Krishnamurthy J,Koivunen J,Chirieac LR,Padera RF,Bronson RT,Lindeman NI,Christiani DC,Lin X,Shapiro GI,Jänne PA,Johnson BE,Meyerson M,Kwiatkowski DJ,Castrillon DH,Bardeesy N,Sharpless NE,Wong KK CONTRIBUTOR Jessica Robertson CONTRIBUTOR_ORG MSigDB Team EXACT_SOURCE Fig 5S: Cluster B FILTERED_BY_SIMILARITY EXTERNAL_NAMES_FOR_SIMILAR_TERMS EXTERNAL_DETAILS_URL SOURCE_MEMBERS C2,Cxcl13,Dcn,Fgfr1,Fn1,Itgbl1,Loxl1,Loxl3,Lum,Mmp2,Ncam1,Nedd9,Pdgfrb,Thbs2,Timp1,Vegfc,Wnt2 GENE_SYMBOLS C2,CXCL13,DCN,FGFR1,FN1,ITGBL1,LOXL1,LOXL3,LUM,MMP2,NCAM1,NEDD9,PDGFRB,THBS2,TIMP1,VEGFC,WNT2 FOUNDER_NAMES