The "No Hit" Model of Cancer Development

Cancer is estimated to contribute to approximately one quarter of all deaths in the United States, according to the most recent statistics from the Centers for Disease Control and prevention. Cancerous cells of various types can invade and destroy tissues throughout the body and may eventually lead to death with or without a therapeutic intervention. The manifestation of cancer is often described as a series of genetic mutations that culminate into uncontrolled cellular growth. That is, the mutation and loss of "tumor suppressing" genes and/or the activation of "oncogenes", also by genetic perturbation. However, a new study published in the journal Nature Genetics suggests that small changes in expression, rather than just genetic perturbations, can also contribute to oncogenesis.

The authors studied the phosphatase and tensin homolog (PTEN) gene in the development of spontaneous tumors in mice. PTEN is a haploinsufficenct tumor suppressor, that is, one copy of the gene is not sufficient to suppress tumor formation. This is in contrast to the tumor suppressing Retinoblastoma gene, in which both copies must be lost for oncogenesis. Although the loss of one PTEN copy can lead to the predisposition to cancer, and hence the moniker haploinsufficient, little is known about what a small reduction in the expression of genes of this nature mean in the frame of cancer susceptibility.

PTEN hypermorphic mice, mice with reduced expression of PTEN without the loss of either allele, were generated by the authors. These mice expressed approximately 80% of the amount of PTEN found in wild type mice. Interestingly, PTEN hypermorphic mice demonstrated an increased accumulation of sporadic mammary tumors and decreased overall survival in comparison to wild type controls. However, the survival rate was greater and the level of tumor formation was less in the hypermorphic mice than in PTEN heterozygous mice. This suggests that a modest decrease in PTEN expression can increase the risk of tumor formation and reduce survival, although not as robustly as a loss of function mutation that leads to the complete ablation of one copy of the gene.

The authors assessed the transcriptional profile of hypermorphic PTEN cells and observed a significant increase in several genes involved in the cell cycle and proliferation. This suggests that a small change in PTEN can have dramatic effects on growth. Interestingly, the same genes were found to be elevated in breast cancer samples with PTEN expression that were reduced from, but greater than 65% of normal levels.

The authors suggest a new model of "No Hit" cancer development in which predisposition occurs when certain tumor suppressors are reduced in expression, but not lost by mutation. This model is interesting in that it suggests a new approach in thinking about cancer susceptibility. In addition to understanding how differences in DNA sequences can be associated with cancer, the level of expression also needs to be considered. While this phenomenon may theoretically only occur with haploinsufficenct tumor suppressing genes, it places an emphasis on understanding events that may regulate the expression of these genes. Such events may include epigenetic modification or input from environmental cues. The work also suggests that genes may have a threshold level for oncogenesis. Determining a threshold level of a gene for increased cancer risk would ultimately have implications for screening and cancer prevention.

References:

Cancer Facts and Figures for 2009. American Cancer Society. http://www.cancer.org/docroot/stt/stt_0.asp. Accessed 5/28/2010.

Subtle variations in Pten dose determine cancer susceptibility. Alimonti A, et, al. Nat Genet. 2010 May;42(5):454-8.