M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan

Mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) tumor suppressor-gene mutation is an early event in human hepatocellular carcinoma (HCC) formation in the United States, but its role in hepatocarcinogenesis in Japan is unclear. We therefore determined M6P/IGF2R mutation frequency in HCCs from patients who resided in the southern, central, and northern regions of Japan. Ten single nucleotide polymorphisms were used to identify HCCs and dysplastic liver nodules with M6P/IGF2R loss of heterozygosity. The retained allele in these tumors was also assessed for point mutations and deletions in the M6P/IGF2R ligand binding domains by direct sequencing of polymerase chain reaction (PCR) amplified DNA products. Fifty-eight percent (54 of 93) of the patients were heterozygous at the M6P/IGF2R locus, and 67% (43 of 64) of the HCCs and 75% (3 of 4) of the dysplastic nodules had loss of heterozygosity. The remaining allele in 21% of the HCCs contained either M6P/IGF2R missense mutations or deletions, whereas such mutations were not found in the dysplastic lesions. In conclusion, M6P/IGF2R is mutated in HCCs from throughout Japan with a frequency similar to that in the United States. Loss of heterozygosity in dysplastic liver nodules provides additional evidence that M6P/IGF2R haploid insufficiency is an early event in human hepatocarcinogenesis.