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Duke Team IDs Recurrence Risk Signatures in Subsets of Non-Small Cell Lung Cancer Patients

By Andrea Anderson

NEW YORK (GenomeWeb News) – In a paper appearing online today in the Journal of the American Medical Association, a Duke University-led research team identified age- and sex-specific gene expression profiles corresponding to higher or lower risk of cancer recurrence in non-small cell lung cancer patients.

"What we were able to do was identify patients at high risk for poor outcomes and poor survival and tease apart pathways that tend to be more active in those patients," co-lead author Marvaretta Stevenson, a hematology and oncology fellow in Anil Potti's laboratory at Duke University, told GenomeWeb Daily News.

Non-small cell lung cancer is the most common type of lung cancer, accounting for some 85 percent or more of lung cancer cases. With a five year survival rate of just 15 percent, researchers are keen to use gene expression and other genomic and clinical information to come up with ways to improve lung cancer diagnosis, prognosis, and treatment.

For instance, Ontario researchers reported last winter that they had identified a six-gene signature that offered insights into NSCLC survival. Meanwhile, in a paper published this past August, a British-led team used gene expression data to come up with an assay to help predict NSCLC drug response.

For the latest paper, researchers focused on combining gene expression profiles with other clinically relevant data — specifically a patient's age and sex — to find pathways involved in cancer recurrence risk in these subgroups.

"Despite evidence that clinical and pathologic factors … are clinically relevant, little is known regarding the underlying biological differences in lung tumor gene expression among patients with different clinicopathologic characteristics," the researchers wrote.

"A deeper understanding of molecular abnormalities at a pathway level may help dissect the complex mechanisms of lung cancer oncogenesis, shed light on the biological underpinnings contributing to survival differences in NSCLC that are age- and sex-based, and further help identify specific cohorts of patients that may be more susceptible to novel individualized therapeutic strategies," they added.

To do this, the team combined gene expression data for 787 NSCLC tumors from four previously published studies. Most of the data was generated using the Affymetrix Human Genome U133A GeneChips microarray, though the researchers used Chip Comparer to convert U95A GeneChip to U133A data for 125 samples before analyzing the results.

When they looked at the gene expression patterns in four patient groups — one containing individuals younger than 70 years old, another containing those who were 70 years old or older, a group of male patients, and a group of female patients — the team found distinct gene expression signatures within these sub-groups.

For instance, the researchers' analyses suggest that patients younger than 70 years had lower risk cancers and better recurrence-free survival than their older counterparts. These younger individuals also tended to have tumors with high expression of genes in pathways involving Src, invasiveness, and beta-catenin pathways.

Within the younger patient group, individuals with a higher risk of recurrence more often had elevated Src and tumor necrosis factor expression in their tumors compared with lower risk individuals.

On the other hand, older patients who had higher recurrence risk often had tumors with higher expression of genes involved in wound healing and invasiveness.

Such findings may prove useful in treating lung cancer in the future, Stevenson noted. Although doctors are sometimes hesitant to treat lung cancer aggressively in elderly patients, she explained, being able to accurately classify older individuals at high risk of recurrence could help target aggressive treatment to those who need it most.

The team also found differences between men and women involved in the study. Women in the high recurrence risk group tended to have tumors with elevated expression of invasiveness and STAT3 signaling pathways. Men at high risk of recurrence, on the other hand, frequently had tumors expressing high levels of genes in the STAT3, tumor necrosis factor, wound healing, and EGFR pathways.

Although women account for some 30 to 40 percent of newly diagnosed lung cancer cases, women tend to have somewhat better NSCLC outcomes than men, Stevenson said, though the reasons are not clear. The new findings suggest pathways linked to poor NSCLC outcomes in men may, in part, explain some of the risk differences between men and women, the authors proposed.

Down the road, such findings may have implications both for finding ways to use existing cancer therapies most beneficially for finding targets for new cancer treatments, co-lead author William Mostertz, a research associate in Potti's Duke University lab, told GWDN. Mostertz said the researchers are currently doing laboratory-based experiments aimed at teasing apart the differences between some of the high- and low-risk pathways identified in the current paper.

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