Researchers Find Genetic Markers for Lung Cancers More Likely to Recur

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Title: Researchers Find Genetic Markers for Lung Cancers More Likely to Recur
URL: http://www.pslgroup.com/dg/21E552.htm
Doctor's Guide
March 14, 2008

BALTIMORE, Md -- March 13, 2008 -- Researchers at the Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, have uncovered clearly recognizable genetic alterations in tumours and tissue removed from patients with early-stage lung cancers -- alterations that look like good predictors of which cancers are more likely to recur. This discovery could change the approach to treating even the smallest, pea-sized lung cancers, which are known to recur within 5 years in 30% to 40% of patients.

"This is DNA forensics for cancer," said Malcolm Brock, MD, Associate Professor of Surgery at Johns Hopkins University, Baltimore, Maryland. "While there may be no trace of cancer that we can spot after surgery with a microscope, the DNA evidence from these tumours may have been left at the scene, especially in lymph nodes."

The particular molecular flags the team identified were chemicals known as methyl groups, which latch on to the DNA ladder structure of a gene. This phenomenon, called methylation, serves as a signal to cells to switch certain genes on or off. Disruption in these signals may create a cascade of abnormal proteins that lead to cancer or its recurrence.

In this study, published in the March 13 issue of The New England Journal of Medicine, Dr. Brock and his team reported how they combed through more than 700 surgical samples from 167 patients with early-stage, non-small-cell lung cancer searching for specific methylation patterns linked to the disease. Tumour and lymph node tissue from 51 patients whose cancers recurred within 40 months were compared with samples from the remaining 116 patients, whose cancers did not recur.

The scientists tested all the samples for methylation on 7 genes linked to the development of lung cancer. Four of these genes -- p16, H-cadherin, APC, and RASSF1A -- showed the highest amounts of methylation in patients whose cancers recurred.

For many of the genes, the study revealed a twofold difference in methyl marks between recurrent cancers and those that did not return. "The DNA evidence we see for many of the recurring cases suggests it may be wise if our work is confirmed to reclassify such cancers as advanced disease instead of early-stage," said Dr. Brock.

Dr. Brock and his colleagues also found that cancers returned even more swiftly than average for 11 patients who had higher than normal methylation in a deadly combination of 2 genes (p16 and H-cadherin) located in both tumour tissue and a lymph node distant from the original tumour area. Eight of the 11 patients with this methylation pattern had cancers that returned within a year. By 30 months, the cancer also recurred in the remaining 3 patients.

The investigators analysed the results to quantify the odds that a particular patient's cancer would recur, noting a 5- to 25-fold increase in risk, depending on the particular methylation pattern. They cautioned that while some of the gene markers lack statistical significance because of small sample size, odds predictions are valid for the 2 most promising genes -- p16 and H-cadherin.

Kimmel Cancer Center medical oncologist James Herman, MD, commented that if these results are confirmed, it may lead doctors to consider treating high-risk patients more aggressively with chemotherapy after surgery. Dr. Herman also believes that therapies that target these gene patterns by stripping off methyl groups hold promise as well. "These marks of aggressive disease also are themselves targets for therapy."

Additional studies of the methyl markers are underway on patients with lung cancer currently being treated at Johns Hopkins.

SOURCE: Johns Hopkins University Kimmel Cancer Center, Baltimore, Maryland

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