DNA Alterations Occur the Earliest in Lung Cancer Development

DNA Alterations Occur the Earliest in Lung Cancer Development
DNA Alterations Occur the Earliest in Lung Cancer Development

Working with tissue, blood, and DNA from six people with precancerous and cancerous lung lesions, scientists identified what they believe are the very earliest premalignant genetic changes that mark the potential onset of the most common and deadliest form of disease.

In a report on the discovery, published online in Nature Communications (2015; doi:10.1038/ncomms9258), the team says the DNA alterations it uncovered were in premalignant lung lesions known as atypical adenomatous hyperplasia (AAH), and the alterations occurred long before the lesions would acquire the ability to invade surrounding tissue and fulfill the definition of adenocarcinoma of the lung.

"We believe we were able to detect, for the first time, DNA circulating in the blood from precancerous lesions of the lung," said research team member Mariana Brait, PhD, an assistant professor of otolaryngology-head and neck surgery at the Johns Hopkins University School of Medicine in Baltimore, Maryland. "This work is a big step in advancing our knowledge of lung cancer because it could give us a chance to find people at risk early."

Their analysis also showed that different regions of the same lesion had various mutations distinctly associated with good and poor outcomes, and that in patients for whom blood samples were available, circulating DNA evidence of the mutations showed up clearly.

"This study takes detection to a whole new level in terms of size of the lesion," said David Sidransky, MD, professor of oncology and pathology at the Johns Hopkins University School of Medicine, where he is director of head and neck cancer research and a member of Kimmel Cancer Center. "I'm not aware that circulating DNA from precancerous lesions this small has ever been identified before."

Sidransky cautioned that the findings are preliminary, involved only a few patients, and are but a first step in figuring out how DNA testing might be used to detect precancerous changes at their earliest stages. But the knowledge is invaluable, he said, for both understanding the molecular biology of how lung cancer originates and how to use the findings in clinical applications.

According to the American Lung Association, adenocarcinomas are the most frequent subtype of lung cancer and are usually diagnosed after they have spread. The average 5-year survival rate for people with adenocarcinoma is 15%, even with the most advanced chemotherapy, surgery, and other treatments.

The prevailing opinion among lung cancer experts is adenocarcinoma of the lung develops from microscopic lesions that over time accumulate multiple genetic alterations that lead to malignancy.

The problem is many such precancerous lesions regress and disappear after a few years, but some will progress to cancer, said lead author Evgeny Izumchenko, PhD, also of Johns Hopkins.

Further studies are planned to confirm the findings in more lung cancer patients. "We have a glimpse into the future in which we can detect premalignant lesions in the lung before they become tumors," said Izumchenko. "But it is only the beginning of a long road we must travel to figure out how to interpret these discoveries to use them optimally in the clinic."

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