DNA detectives find genetic markers for lung cancers most likely to recur

Mar 13 2008

Researchers at the Johns Hopkins Kimmel Cancer Center have uncovered clearly recognizable genetic alterations in tumors and tissue removed from patients with early-stage lung cancers that look like good predictors of which of these cancers are more likely to recur.

The discovery, they say, could change the approach to treating even the smallest lung cancers - the size of a pea - which are known to recur within five years in 30 to 40 percent of patients.

“This is DNA forensics for cancer,” says Malcolm Brock, M.D., associate professor of surgery at Johns Hopkins. “While there may be no trace of cancer that we can spot after surgery with a microscope, the DNA evidence from these tumors may have been left at the scene, especially in lymph nodes.”

The particular molecular flags the team identified are chemicals known as methyl groups that latch on to the DNA ladder structure of a gene. Methylation is a commonly known phenomenon in the formation and development of cancers because they serve as signals 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 the study published in the March 13 issue of the New England Journal of Medicine, Brock and his team report how they combed through more than 700 surgical samples from 167 early stage, non-small cell lung cancer patients searching for specific methylation patterns linked to the disease.

Tumor 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 seven genes linked to the development of lung cancer. Four of them - 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,” says Brock.

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 two genes known as p16 and H-cadherin located in both tumor tissue and a lymph node distant from the original tumor area. Eight of the 11 patients with this methylation pattern had cancers that returned within a year. By 30 months, the remaining three patients' cancer had also recurred.

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

Kimmel Cancer Center medical oncologist James Herman, M.D. says if these results are confirmed, it may lead doctors to consider treating high-risk patients more aggressively with chemotherapy after surgery. He also believes that therapies which 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 under way on lung cancer patients currently being treated at Johns Hopkins.

Cure rates for lung cancer are far lower than for other common cancers such as breast or prostate. Lung cancer is the deadliest cancer and second most common in the United States.