Monday, July 16, 2012
An interplay between GO genes and STOP genes optimizes cancer growth
Tumor cells typically have certain genes (called oncogenes) that are either mutated or highly expressed (for example, they can increase in copy number) and that promote tumor growth. Oncogenes often act in combination with silenced tumor suppressor genes -- genes that inhibit tumor development. As the name suggests, if both copies of a tumor suppressor gene are silenced, tumor growth is promoted.
To date, there are nearly 500 oncogenes that have been catalogued and whose mutations have been shown to cause cancer. However, when researchers look at the whole genome of a cancer cell, they find thousands of mutations, the vast majority of which does not affect the cancer genes. Some genes present mutations that clearly promote tumorigenesis, but most mutations found in cancer genomes seem to have a cumulative effect on the proliferation of the cancer.
For example, one common change found in tumor cells is the absence of entire DNA loci. Some deletions happen on both chromosome copies, but most common are the ones that happen on one of the copies only. These are called hemizygous deletions and can span up to thousands of genes. They have been found in breast, gastric, bladder, pancreatic, and ovarian cancers, all with an average of more than ten deletions per tumor. One hypothesis of why they are more common than homozygous deletions is that cells where both copies are deleted are more likely to trigger cell apoptosis and other "self-correcting" mechanisms. Also, in some cases, there may be genes nearby that cannot have both copies deleted.
In order to understand the role of these hemizygous deletions in tumorigenesis, Solimini et al.  studied the mutations from whole-genome sequencing of 526 tumors in the Catalogue of Somatic Mutations in Cancer (COSMIC). In their model, they called the tumor suppressor genes STOP genes (genes that inhibit tumor proliferation), and the oncogenes GO genes (genes that promote tumor growth). They found that the majority of deletions were indeed hemizygous and that haploinsufficiency (the loss of one gene copy) of both GO and STOP genes caused by hemizygous deletions is one of the driving forces for cancer growth, and that the effect was cumulative in the number of genes that displayed haploinsufficiency.
A better understanding of these mechanisms may help us target cancer treatment more efficiently.
 Nicole L. Solimini,, Qikai Xu,, Craig H. Merme,, Anthony C. Liang,, Michael R. Schlabach,, Ji Luo,, Anna E. Burrows,, Anthony N. Anselmo,, Andrea L. Bredemeyer,, Mamie Z. Li,, Rameen Beroukhim,, Matthew Meyerson,, & Stephen J. Elledge1 (2012). Recurrent Hemizygous Deletions in Cancers May Optimize Proliferative Potential Science DOI: 10.1126/science.1219580