DNA variants of DLC-1, a candidate tumor suppressor gene in human hepatocellular carcinoma.
The DLC-1 gene encoding a regulator of the Rho family of small GTPases is altered in breast, prostate, colon, and liver cancer and has several characteristics of a tumor suppressor gene. DLC-1 overexpression causes inhibition of in vitro growth of liver tumor cells and complete suppression of in vivo tumorigenicity of breast tumor cells. Inactivation and aberrant expression of DLC-1 in human hepatocellular carcinoma (HCC) is frequently associated with hemizygous and homozygous genomic deletion and promoter methylation. Since inactivation of tumor suppressor genes in cancer cells is also commonly associated with point mutation, we evaluated the incidence of mutation of the DLC-1 gene by PCR-SSCP in 17 primary HCC and 18 HCC cell lines. One missense mutation was detected at codon 991 of exon 12 (C-->T transition, Val-->Ile) in an HCC cell line. In addition, two types of polymorphisms were identified: a G-->T at codon 745 of exon 9, a T-->C at 17 bp downstream of exon 2. While the pathogenic relevance of the intronic polymorphism is not known, the low rate of mutation of the DLC-1 gene in HCC implies that genomic deletion and promoter methylation primarily account for the altered expression and tumor suppressive inactivation of the DLC-1 gene.
Park
Sang-Won
SW
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute/NIH, 37 Convent Drive, Bethesda, MD 20892, USA.
Durkin
Marian E
ME
Thorgeirsson
Snorri S
SS
Popescu
Nicholas C
NC
D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D003062:Codon; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D005091:Exons; D020690:GTPase-Activating Proteins; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006720:Homozygote; D006801:Humans; D007438:Introns; D008113:Liver Neoplasms / Q000235:genetics*; D009154:Mutation; D017354:Point Mutation; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D003062:Codon; C112352:DLC1 protein, human; D018076:DNA, Complementary; D020690:GTPase-Activating Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins