M6P/IGF2R: An Imprinted Tumor Suppressor

Randy Jirtle
Department of Radiation Oncology; Duke University Medical Center

The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) functions in the intracellular trafficking of lysosomal enzymes, the activation of the growth inhibitor, TGFß, and the degradation of the mitogen, IGF2. Thus, this receptor normally functions as a "guardian of the cell" by controlling the extracellular levels of potent growth factors and proteolytic enzymes that govern cell death, proliferation and invasion. We have recently demonstrated that the M6P/IGF2R is also frequently mutated in liver and breast cancer (1-3). Furthermore, the M6P/IGF2R gene contains a poly-G region that is a common mutational target in colon, gastric and endometrial tumors with mismatch repair deficiencies (4). M6P/IGF2R allelic inactivation is an early event in both breast [3] and liver [5] carcinogenesis, occurring during the initiation rather than the progression stage of transformation. Furthermore, in the liver of patients chronically infected with hepatitis virus, inactivation of a single allele of the M6P/IGF2R results in the clonal expansion of normal appearing, preneoplastic hepatocytes from which 60% of human HCCs will ultimately develop. Thus, the M6P/IGF2R is a tumor suppressor gene that is inactivated frequently and early in a variety of cancers.

Although the M6p/Igf2r is imprinted in rodents, imprinting of the M6P/IGF2R is a polymorphic trait in humans [4,6]. The marked species difference in the imprint status of this tumor suppressor gene between mice and humans provides a plausible explanation for the enhanced sensitivity of mice to tumor formation, and also has implications concerning carcinogen risk assessment based on animal models. It also suggests that people who are imprinted at this locus would be predisposed to cancer. (This research was funded in part by NIH grants CA25951and ES08823, DOD grant DAMD17-98-1-8305, Sumitomo Chemical Co., Ltd. and Zeneca Pharmaceuticals, Ltd.)


  1. De Souza, A.T., Hankins, G.R., Washington, M.K., Fine, R.L., Orton, T.C., and Jirtle, R.L. Frequent loss of heterozygosity on 6q at the mannose 6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors. Oncogene 10: 1725-1729, 1995.

  2. De Souza A.T., Hankins, G.R., Washington, M.K., Orton, T.C., and Jirtle, R.L M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nat. Genet. 11: 447-449, 1995.

  3. Hankins, G.R., De Souza, A.T., Bentley, R.C., Patel, M.R., Marks, J.R., Iglehart, J.D., and Jirtle, R.L. M6P/IGF2 receptor: a candidate breast tumor suppressor gene. Oncogene 12: 2003-2009, 1996.

  4. De Souza, A.T., Yamada, T., Mills, J.J., and Jirtle, R.L. Imprinted genes in liver carcinogenesis. FASEB J. 11: 60-67, 1997.

  5. Yamada, T., De Souza, A.T., Finkelstein, S., and Jirtle, R.L. Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis. Proc. Natl. Acad. Sci. USA 94: 10351-10355, 1997.

  6. Mills, J.J., Falls, J.G., De Souza, A.T., and Jirtle, R.L. Imprinted M6p/Igf2 receptor is mutated in rat liver tumors. Oncogene 16 (1998) 2797-2802.