A Better Way to Screen for Lung Cancer

Even though cigarette smoking is on the decline, more people in the U.S. die of lung cancer each year than of colon, breast, and prostate cancers combined. To address this, the American Cancer Society recently introduced more inclusive lung cancer screening guidelines for people who used to or currently smoke.

But lung cancer is notoriously difficult to detect early. Current screening technology is expensive, at times inaccurate, and not as widely recommended by clinicians as it could be. And while a history of smoking is the biggest risk factor for developing lung cancer, up to 20% of lung cancers develop in people who never smoked. The result: lung cancer is frequently diagnosed only when very advanced and treatment options are limited. 

Professor Dominique Michaud at Tufts University School of Medicine and colleagues at collaborating institutions hope to change that, with help from a new $2.5 million, four-year grant from the National Institutes of Health (NIH). Their research seeks to devise a way to detect lung cancers earlier and more accurately, increasing the likelihood that treatments can slow and cure the disease. The researchers are using data from the National Lung Screening Trial (NLST), a large study conducted only with smokers, but their long-term goal is to look at nonsmokers, as well.

The current standard for lung cancer screenings are low-dose CT (LDCT) scans, which are expensive, can produce false positives and negatives, and expose patients to radiation, says Michaud, a professor of public health and community medicine. As a result, only about 10% of people recommended for screening are regularly screened, unlike mammography screening for breast cancer and colonoscopy screening for colorectal cancer, which people are far more likely to do.

A Better Predictor than Smoking

Michaud and colleagues are focusing on a blood test with an array that uses blood leukocytes to measure DNA methylation levels at about 850,000 genomic sites and look for changes in methylation levels at multiple sites. DNA methylation is a genetic process that can be influenced by environmental factors and has been seen as potentially useful in detecting other conditions such as cardiovascular disease. Methylation is a normal process that can control gene expression. In cancer, abnormal methylation patterns can lead to the silencing of genes that suppress tumors or the activation of oncogenes that promote cancer growth.

Michaud previously worked on changes in methylation levels associated with pancreatic cancer risk and then moved on to research focused on methylation and lung cancer. With a multi-million-dollar grant from the American Association of Cancer Research, the researchers reviewed archived blood samples from a longitudinal study called the CLUE cohort study. 

“People had donated blood for this large prospective cohort study, and the samples were stored for many years. We were able to go back and pull the blood that was frozen from participants who were later diagnosed with lung cancer, and we matched them with blood samples from controls who did not develop lung cancer,” Michaud explains. 

Through this effort, Michaud and colleagues discovered new regions where methylation levels were different in people who developed lung cancer than those who did not. They also confirmed research by other scientists that identified areas of differentiation between people who developed lung cancer and who did not.

“These regions have been shown to better predict mortality from lung cancer than smoking,” says Michaud.

Developing A Blood Test

Under the new NIH grant, the Tufts scientists now propose to measure DNA methylation levels in blood leukocytes obtained from samples that were collected at multiple times from the NLST.

“We want to develop a pre-screening tool that would accurately classify people we already know are at high risk into additional risk categories based on their level of methylation,” says Michaud. If successful, this could result in changes to screening guidelines and help reduce the number of scans needed to detect lung cancer. 

The team also wants to determine whether differences in DNA methylation markers can distinguish participants with positive LDCT screening results from people who have cancer from those with false positives. And they hope to see if differences in DNA methylation markers can discriminate between participants who had a negative scan and did not have cancer from those with false negative scans who were diagnosed with lung cancer during follow-ups.

“We believe a blood test using DNA methylation markers could be a better way to stratify cancer risk among people we know are already at higher risk because of their smoking history,” Michaud says. “One way to test this hypothesis is by using archived samples that were collected decades ago from which researchers already know who tested positive using LDCT scans, and who actually developed lung cancer subsequently.”

“Our goal is to identify an effective blood test that can reduce unnecessary scans in the future and help us identify true positive and false negative LDCT scans,” Michaud says.

In addition to smoking, researchers believe other known factors that cause lung cancer, such as exposure to secondhand smoke, radon, asbestos, air pollution, or other substances, may also impact methylation levels. Different environmental exposures might combine to result in someone having different methylation levels in key genomic regions, putting them at higher risk for lung cancer even though they might be overlooked by screening guidelines because their risk is not defined by smoking history.

“We know genetic regions that show higher levels of methylation if someone is a smoker,” says Michaud. “But now we can look at those regions in people who are not at high risk and are not heavy smokers. By improving risk prediction models with these biomarkers, we may ultimately reduce disparities and increase the effectiveness of lung cancer screening across a broader spectrum of people that includes nonsmokers and never smokers.”

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