The overall research object of the laboratory is to determine the role of genomic imprinting in carcinogenesis. Each cell contains both maternal and paternal copies of all genes except those that reside on the sex chromosomes, however, because of a phenomenon termed genomic imprinting, not all genes are biallelically expressed. Imprinted genes play an important role in embryogenesis, and recently have also been shown to be mechanistically involved in carcinogenesis (1-3). A number of genes have been shown to be imprinted, and we were the first to demonstrate that the imprinted mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) gene is a tumor suppressor (4-6).

The M6P/IGF2R functions in the activation of the potent growth inhibitor, transforming growth factor beta (TGFß), and the degradation of IGF2, a mitogen often overproduced in tumors. We have demonstrated that the M6P/IGF2R is often mutated in dysplastic liver lesions and hepatocellular carcinomas (HCCs) in patients with or without hepatitis virus (HV) infection (1,4,6). Furthermore, in HV-infected patients M6P/IGF2R inactivation has already occurred in the phenotypically normal tissue adjacent to these dysplastic lesions and HCCs (4). This demonstrates that M6P/IGF2R inactivation occurs early rather than late in liver carcinogenesis, and that the liver of chronic HV-infected people consists of large clones of normal appearing M6P/IGF2R-mutated precancerous liver cells from which liver tumors ultimately develop. It is because of this large increase in precancerous liver cells that HV-infected patients have an enhanced risk of developing HCC. The M6P/IGF2R has also been shown to be frequently mutated in breast cancer (5) and in colon, gastric and endometrial cancers with mismatch repair defects (1). We are presently determining whether this tumor suppressor gene is also involved in the genesis of ovarian and lung cancer.

Mice are imprinted at the M6P/IGF2R locus. In contrast, imprinting of the M6P/IGF2R is a polymorphic trait in humans with most people having biallelic expression (1-3). Genomic imprinting of the M6P/IGF2R in only a small percentage of people would be expect to result in a non-Mendelian inherited predisposition to cancer. Furthermore, the marked species difference in M6P/IGF2R imprinting between mice and humans provides a plausible explanation for the enhanced sensitivity of mice to tumor formation (3). These intriguing postulates are being investigated and additional imprinted genes are being identified in our laboratory.

Selected Publications:

1. Jirtle Genomic imprinting and cancer. Exp. Cell Res. 248: 18-24, 1999.

2. Falls et al. Genomic Imprinting: Implications for Human Disease.
Am. J. Pathol. 154: 635-647, 1999. [Full Text]

3. Pulford et al. Polymorphisms, genomic imprinting and cancer susceptibility.
Mutat. Res. 436: 59-67, 1999.

4. Yamada, T., et. al. 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. 94: 10351-10355, 1997. [Full Text]

5. Hankins, G.R., et. al. M6P/IGF2 receptor: a candidate breast tumor
suppressor gene. Oncogene 12: 2003-2009, 1996.

6. De Souza, A.T., et. al. M6P/IGF2R gene is mutated in human
hepatocellular carcinomas with loss of heterozygosity. Nature Genet. 11: 447-449, 1995.