Epigenetic Activity Silences Tumor Suppressing Gene In Lung Cancer

Their findings are reportedin two studies: "Tumor-specific exon 1 mutations could be the 'hitevent' predisposing Rb2/p130 gene to epigenetic silencing in lungcancer" and "Genetic and epigenetic alterations of RB2/p130 tumorsuppressor gene in human sporadic retinoblastoma: implications forpathogenesis and therapeutic approach," both of which appear inSeptember issues of Oncogene (www.nature.com/onc).

The jointstudies at Temple and Siena were coordinated by Antonio Giordano, M.D.,Ph.D., director of Sbarro Institute at Temple (www.shro.org), and byMarcella Macaluso of the Sbarro Institute and Caterina Cinti of bothCentro Nazionale Ricerche and the University of Siena.

Giordanosaid that the researchers were puzzled when they found Rb2/130, thetumor suppressing gene discovered by Giordano in the early 1990s, in anepigenetic state in both the NSLC and retinoblastoma cells. In thisepigenetic state, the gene showed no signs of mutation, but is silentin its expression or function.

Further examination of the genefound that it had been methylated, a process in which methyl orchemical groups attached themselves to the gene, attacking a sequenceof the Rb2/p130's DNA and thus causing it to cease functioning.

"Thesestudies are providing very important information on how cancerous andpre-cancerous conditions can be detected by the presence of themethylated state of Rb2/p130," said Giordano. "These cancerous orpre-cancerous conditions can be treated with drugs or agents thatde-methylate the Rb2/p130 gene. Once the drugs or agents disconnect themethyl groups from Rb2/p130, the gene begins to again express itself orfunction normally."

He likened this methylation/de-methylationphenomenon--which can stop or start the expression of a gene--to alightswitch which is used to turn a lamp off or on.

Giordano saidsome of these agents that will de-methylate Rb2 are already available,but have not been previously used because researchers did not know thatthe lack of expression from the gene was being caused by itsmethylation.

"Our discovery is providing a smart method toidentify novel methylated drugs or agents that can assist in restartingthe vital expression of Rb2/p130," he said.

Through the use of asimple genetic (both at DNA and Protein level) test of Rb2 gene andprotein from a human tissue sample, said Giordano, scientists coulddetermine if cancerous or pre-cancerous conditions exist because of theepigenetic state of the gene.

"We could develop a potential test which could save many, many people from the ravages of cancer," he said.