M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan
Article first published online: 30 DEC 2003
Copyright © 2002 American Association for the Study of Liver Diseases
Volume 35, Issue 5, pages 1153–1163, May 2002
How to Cite
Oka, Y., Waterland, R. A., Killian, J. K., Nolan, C. M., Jang, H.-S., Tohara, K., Sakaguchi, S., Yao, T., Iwashita, A., Yata, Y., Takahara, T., Sato, S.-i., Suzuki, K., Masuda, T. and Jirtle, R. L. (2002), M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan. Hepatology, 35: 1153–1163. doi: 10.1053/jhep.2002.32669
- Issue published online: 30 DEC 2003
- Article first published online: 30 DEC 2003
- Manuscript Accepted: 29 JAN 2002
- Manuscript Received: 19 NOV 2001
- NIH. Grant Numbers: CA25951, ES08823
- Sumitomo Chemical Company, Ltd.
- AstraZeneca Pharmaceuticals, Ltd.
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.