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Study of Normally Silent Somatic Tissue Genes Leads to Potential Prognostic Signature in Lung Cancer

NEW YORK (GenomeWeb News) – A study published online yesterday in Science Translational Medicine suggests that expression levels at around two-dozen genes not normally active in somatic cells can help distinguish aggressive or metastasis-prone lung cancers from lower-risk tumors.

A research team led by investigators at the French National Institute of Health and Medical Research (INSERM) used expression and epigenetic profiles from normal tissues to home in on normally silent genes that become activated in a range of cancers.

"We designed a strategy for investigating [epigenetic reprogramming]," INSERM's Saadi Khochbin, senior author on the study, and colleagues wrote, "which consisted of identifying a large number of tissue-restricted genes that are epigenetically silenced in normal cells and then detecting their expression in cancer."

For lung cancer, that analysis — coupled with analysis of tumor samples from almost 300 lung cancer patients — helped the group narrow in on 26 genes that are prone to activation in lung cancer tumors from individuals with metastases and/or particularly poor outcomes.

Follow-up experiments revealed that the number of genes that are highly expressed from the signature are informative, too: individuals with higher-than-usual expression at three or more of the genes had especially low survival and higher risk of lung cancer metastasis.

"Our findings leave room for speculations and new investigations," Khochbin and colleagues noted, "but the very typical and homogeneous clinical, biological, and molecular portrait of aggressive tumors identified with this 26-gene signature implies that they might be associated with fundamental oncogenic mechanisms, which cooperate to generate such aggressive tumors."

The group credited the apparent success of their new analysis, in part, to past work done to discern typical expression patterns in various tissues, making it possible to see the sorts of genes that are expressed in cells that have strayed from their normal, tissue-specific programs.

"A key to this finding was the previous definition of tissue-restricted gene expression, which identified a specific category of genes that are normally expressed in the germline and placenta," the group explained, "and present a characteristic 'locked' configuration in all non-germline cell types, including embryonic stem cells."

"The large-scale activation of this specific category of silenced genes in all cancers primarily reflects a general loss of cell identity," they added, "most likely due to a profound transformation of their overall epigenetic landscape."

For their analysis, the researchers sifted through existing expressed sequence tag, transcriptome, sequence, and epigenetic data in an effort to find genes normally silenced in somatic cells and tissues that might be prone to a loss or repression in cancer.

The search led to a set of more than 500 genes typically expressed in germline cells or placental tissue. The same genes are not expressed in normal somatic tissues, the team noted, apparently due to epigenetic silencing.

When they looked at the expression of these so-called 'testis-specific/placenta-specific,' or TS/PS, genes in 1,776 tumors samples from individuals with 14 types of cancer, investigators found that hundreds of the genes did, indeed, show a cancer-related jump in expression.

After assessing TS/PS gene expression in a few other cancer types, the teams went on to look specifically at the expression of such genes in lung cancer, testing tumor samples from 293 individuals with the disease.

Again, gene expression analysis picked up more active than usual TS/PS genes in the lung cancer tumors, researchers reported. When they added in lung cancer patients' survival information, they found that expression profiles at 26 of the TS/PS genes corresponded to survival outcomes.

That was especially true for the 152 individuals who had early stage lung cancer when their tumors were first tested.

The association with survival hinged, in part, on the number of survival signature genes showing altered expression, the team found.

For instance, those with elevated expression at three or more of the 26 signature genes were prone to both metastasis and particularly poor survival outcomes, whereas those with heightened expression at one or two of the genes tended to be at intermediate risk.

Follow-up experiments in another 61 patients supported the notion that the 26-gene signature has prognostic potential in lung cancer.

By further studying tumors from individuals from that group who were deemed to be at high risk based on expression patterns at the 26 genes, meanwhile, researchers unearthed thousands more genes with higher- or lower-than-usual expression in poor prognosis tumors — expression patterns expected to provide clues about the pathways altered in those aggressive lung cancers.

That, in turn, supports the notion that the type of "off-context" gene expression profiling performed in the study might present researchers with biomarker candidate genes as well as new paths to explore with regard to lung cancer biology and treatment.

"The methodical recognition of ectopic gene activations in cancer cells could serve as a basis for gene signature-guided tumor stratification," they wrote, "as well as for the discovery of oncogenic mechanisms, and expand the understanding of the biology of very aggressive tumors."