City of Hope investigators have taken a significant step toward developing diagnostics to detect a type of lung cancer — the top cancer killer — by identifying a battery of markers that could be used in relatively simple tests.
A team led by Gerd Pfeifer, Ph.D., Lester M. and Irene C. Finkelstein Chair in Biology, and Arthur Riggs, Ph.D., professor of biology and Beckman Research Institute director emeritus, used a method developed in Pfeifer’s lab to pinpoint chemical modifications related to lung cancer in the DNA of chromosomes 7 and 8. They published the findings in the Jan. 8 issue of Proceedings of the National Academy of Sciences (PNAS).
Comparing DNA from tumor cells of patients with lung squamous cell carcinoma to DNA from normal lung tissue, the team identified 11 genes in the cancer cells’ DNA that had been modified by methyl groups. This modification, known as hypermethylation, was found in three genes of every tumor evaluated.
The striking consistency makes these markers excellent candidates to detect cancer. “People have tested a few genes before and found they were methylated in only about 40 to 50 percent of tumors,” Pfeifer said. “The advance here is that these new markers are methylated in 80 to 100 percent of tumors, so you are not likely to miss something.”
The molecular markers’ high sensitivity could allow individuals to be evaluated less invasively, possibly by analyzing tiny amounts of DNA in the blood or in mucous from lungs.
“These findings could let us assess the status of lung squamous cell carcinoma after chemotherapy, surgery or radiation treatment,” said Kemp Kernstine, M.D., Ph.D., director of the Lung Cancer and Thoracic Oncology Program and a collaborator on the study.
“We could potentially use the biomarkers to diagnose cancer following a suspicious chest X-ray or computed tomography scan. Or we could use them to screen for cancer before it shows up on a scan or X-ray.”
Another significant finding reported in the paper is that methylation of stretches of highly repeated DNA in the human genome was lower in lung tumors than in normal tissues. Lead author Tibor Rauch, Ph.D., a postdoctoral fellow in Pfeifer’s lab, noted that some repetitive DNA sequences are capable of moving around on chromosomes, but methylation halts that movement. Many researchers believe that chromosomal changes, or “instability,” are a major cause of cancer.
Riggs finds the undermethylation results intriguing. “At the same time that we identify hypermethylated genes, we find undermethylated repetitive sequences,” he said. “This is of crucial importance to our understanding of cancer and probably also of normal development.”
Squamous cell carcinoma in the lungs, caused primarily by smoking, is the second most common lung cancer. Having better methods to diagnose it and all lung cancers early could save lives: Only 16 percent of the estimated 170,000 cases of lung cancer diagnosed each year are detected early enough for successful surgical removal.
Additional study participants were Zunde Wang, Ph.D., Melody Wang and Xueyan Zhong from the Division of Biology, and Xiwei Wu, Ph.D., from the Division of Information Sciences.
The National Institutes of Health funded the research.