Scientists Identify DNA Alterations As Among Earliest To Occur In Lung Cancer Development

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Nov 2, 2015

2043

Lungs Cancer

In a report published recently in Nature Communications, researchers from John Hopkins have revealed that they have discovered what they believe to be among the very earliest premalignant genetic changes that mark the potential onset of the deadly lung cancer.

The team of scientists was working with tissue, blood and DNA from six people with precancerous and cancerous lung lesions. The DNA alterations they have uncovered were in premalignant lung lesions known as atypical adenomatous hyperplasia, or AAH. These alterations took place long before the lesions would become malignant and invade surrounding tissue and fulfill the definition of adenocarcinoma of the lung.

Mariana Brait, Ph.D., a member of the research team, an assistant professor of otolaryngology-head and neck surgery at the Johns Hopkins University School of Medicine said that they believe that what they have detected for the first time is the DNA circulating in the blood from precancerous lesions of the lung. This discovery could give a chance to find people at risk of lung cancer early. Their analysis also revealed 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.

David Sidransky, M.D., professor of oncology and pathology at the Johns Hopkins University School of Medicine and the director of head and neck cancer research at Johns Hopkins opined that this study takes detection to a whole new level. Sidransky cautions that even though the findings are preliminary and involved only a few patients, it shows promise about how DNA testing might be used to detect precancerous changes at their earliest stages.

Statistics from the American Lung Association reveal that adenocarcinomas are the most frequent subtype of lung cancer and are typically diagnosed after they have spread. Even with the most advanced chemotherapy, surgery and other treatments, average five-year survival rate for people with adenocarcinoma is merely 15 percent. It is believed by experts that adenocarcinomas of the lung develop from microscopic lesions that accumulate multiple genetic alterations over time that then lead to malignancy.

Evgeny Izumchenko, Ph.D., a postdoctoral fellow in Sidransky’s laboratory and the lead author of the study said that in many cases the precancerous lesions regress and disappear after a few years, but some will progress to cancer. To find out which factors make the lesions turn into cancer, the team studied tissue samples from six patients undergoing surgical removal of lung tumors. Then William Westra, M.D., professor of pathology, went through the tissue samples to single out tiny precancerous AAH lesions in the lung tissue for study. The scientists then extracted and sequenced DNA from these AAH lesions, as well as from other adenocarcinomas in situ, minimally invasive adenocarcinomas and fully invasive adenocarcinomas”an array of lesions that represent the progression from AAH to fully invasive adenocarcinoma.

Using a DNA sequencing technique they next looked for mutations in 125 genes known to play a significant role in cancer development and advancement. When the DNA of the premalignant lesions was compared with DNA isolated from primary invasive cancer within each patient, the sequencing showed that in three of the patients, the same mutations were shared between the premalignant lesions and the tumor from the same patient. Izumchenko opined that it suggests that these mutations could be the drivers of tumor progression.

Their study also revealed that lung cancer can be initiated by disturbances in different molecular pathways since they found that different AAH lesions from different patients had unique patterns of mutations. Also, it was found that there could be differences even within the same lesion. Further findings also suggest that a blood or sputum test could better represent the overall composition of a tumor than a single biopsy sample. The results of the study are promising “ further studies are planned involving more lung cancer patients to confirm the findings.