Methylation of the promoter region of four genes in tumor and histologically negative lymph nodes predicts early postoperative recurrence of stage I non-small cell lung cancer, according to an article in the March 13 issue of the New England Journal of Medicine.

"This is DNA forensics for cancer," said Malcolm Brock, MD, associate professor of surgery at Johns Hopkins Kimmel Cancer Center and study lead author. "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."

In the current work, researchers evaluated more than 700 surgical samples from 167 patients with stage I non-small cell lung cancer to identify any specific methylation patterns linked to early postoperative recurrence. Tumor and histologically negative lymph node tissue from 51 patients whose cancers recurred within 40 months were compared with samples from 116 patients whose cancers did not recur in that time frame.

The scientists evaluated seven genes linked to development of lung cancer. Four of them - p16, H-cadherin, APC and RASSF1A - showed highest amounts of methylation in patients whose cancers developed early recurrence.

For many of the genes, the study revealed a twofold difference in methylation between recurrent cancers and those that did not recur.

"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 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 the two genes p16 and H-cadherin located in both tumor tissue and a distant lymph node. Of the 11 patients with this methylation pattern, 8 had cancers that returned within one year. By 30 months, the remaining three patients' cancer had also recurred.

The investigators quantified the likelihood 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 lacked statistical significance because of small sample size, odds predictions were valid for the two most promising genes - p16 and H-cadherin.

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