Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis.
This report shows that loss of heterozygosity at the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) locus occurred in 5/8 (63%) dysplastic liver lesions and 11/18 (61%) hepatocellular carcinomas (HCCs) associated with the high risk factors of hepatitis virus infection and liver cirrhosis. Mutations in the remaining allele were detected in 6/11 (55%) HCCs, including deletions in a polydeoxyguanosine region known to be a target of microsatellite instability. M6P/IGF2R allele loss was also found in cirrhotic tissue of clonal origin adjacent to these dysplastic lesions and HCCs, demonstrating that M6P/IGF2R inactivation occurs early in liver carcinogenesis. In conclusion, HCCs frequently develop from clonal expansions of phenotypically normal, M6P/IGF2R-mutated hepatocytes, providing further support for the idea that M6P/IGF2R functions as a liver tumor-suppressor gene.
Yamada
T
T
Environmental Health Science Laboratory, Sumitomo Chemical Company, 3-1-98, Kasugade-Naka, Konohana-Ku, Osaka 554, Japan.
De Souza
A T
AT
Finkelstein
S
S
Jirtle
R L
RL
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002872:Chromosome Deletion; D005260:Female; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017527:Receptor, IGF Type 2 / Q000235:genetics*; D012307:Risk Factors
D017527:Receptor, IGF Type 2