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CYCLOPS genes represent a specific form of synthetic lethality

CYCLOPS genes represent a specific form of synthetic lethality

Scientists have identified 56 genes that are vital to cancer cell survival and may represent accessible targets for therapeutic development. In each case only one copy of the target gene is present in the cancer cell due to copy number loss resulting from genomic instability. This study represents a bringing-together of two approaches to understanding the basic mechanics of cancer. One involves research into the effect of gene copy number changes on cancer. The other is a systematic exploration of the function of individual genes. This important finding has been published in the August 17, 2012 issue of Cell under the title, “Cancer Vulnerabilities Unveiled by Genomic Loss”. The team first analyzed the copy number profiles of over 3,100 samples and found that most of them exhibited copy number loss affecting at least 11%, and up to 40% of their genomes. The team then combined their data with those from project Achilles (A Dana-Farber initiative that has identified hundreds of genes critical to cancer cell proliferation). From a starting set of over 5,000 genes, they identified 56 for which loss of one copy in a cancer cell rendered the remaining copy essential to cancer cell survival. At the top of this list there are 56 designated CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss) genes in terms of dependence of cancer cells on the proteasome gene PSMC2 [Proteasome (prosome, macropain) 26s subunit, ATPase, 2]. One copy of this gene was frequently lost in the hitherto evaluated cancer cells. However, but the above gene was never found to be missing altogether, indicating that at least one copy was essential for cell survival. To verify the importance of PSMC2 in vivo, the team blocked the remaining copy of the gene in mice carrying tumors that already lacked one copy of PSMC2. The result was dramatic tumor shrinkage. It was a powerful demonstration of the potential of CYCLOPS genes to serve as targets for cancer therapy. The researchers describe that CYCLOPS genes represent a specific form of synthetic lethality, a phenomenon through which the combination of mutations in two or more genes leads to cell death, whereas a mutation in either one alone does not. This opens up a potentially large variety of vulnerabilities to attack cancer cells. There is still a long way to go before this phenomenon can be utilized therapeutically. The results so far obtained indicate that it has potentially a widespread application. [summarized by a graduate student Samsad Razzaque]

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