Circulating tumor DNA (ctDNA) is a promising biomarker in oncology. ctDNA carries genetic information from malignant tumors and can be obtained from peripheral blood samples. A team of Johns Hopkins scientists worked with tissue, blood and DNA from six people with precancerous and cancerous lung lesions, and identified DNA alterations that were in premalignant lung lesions. These alterations known as atypical adenomatous hyperplasia or AAH occurred long before the lesions would acquire the ability to invade surrounding tissue and fulfill the definition of adenocarcinoma of the lung.
Adenocarcinomas represent the most frequent subtype of lung cancer and they are usually discovered late in the course of the disease. According to the Cancer Treatment Centers of America, non-small cell lung cancer (NSCLC) accounts for 80 percent of lung cancers and adenocarcinoma is the most common type.
Lung cancer experts say that adenocarcinomas of the lung develop from microscopic lesions that accumulate multiple genetic alterations over time that then lead to malignancy. While some of the precancerous lesions regress and disappear after a few years, others will progress to cancer. Tissue samples from six patients undergoing surgical removal of lung tumors were evaluated to predict which of these small lesions progress to lung cancer. The steps involved were:
- Evaluation of the tissue samples millimeter by millimeter to distinguish tiny precancerous AAH lesions in the lung tissue for study
- DNA was extracted and sequenced from these AAH lesions and from other adenocarcinomas in situ
- Using targeted next-generation sequencing technique, the team looked at mutations in 125 genes, which play a significant role in cancer development and progression
- DNA of the premalignant lesions was compared with DNA isolated from primary invasive cancer within each patient
It was found that in three of the patients, the same mutations were shared between the premalignant lesions and the tumor from the same patient. According to a researcher, “This is the first definitive link ever found between potential premalignant lesions and invasive tumors in the same lung, and it suggests that those mutations may be the drivers of tumor progression.”
Other key findings are:
- Different AAH lesions from different patients had unique patterns of mutations. This indicates that lung cancer can be initiated by disturbances in different molecular pathways.
- Some of the lesions were “dead ends,” and most likely were insufficient to progress to full-blown cancer.
Another experiment done by the researchers indicate that sputum or blood testing could better represent the overall composition of a tumor than a single biopsy sample. With the blood plasma and sputum taken from two patients, the researchers extracted DNA and used digital polymerase chain reaction to look for the same mutations they had found in each patient’s biopsy samples.
The study is only an initial step in figuring out how DNA testing might be used to detect precancerous changes at their earliest stages; the findings are preliminary and involved only a few patients. The team has planned further studies to confirm the findings in more lung cancer patients. The leading author of the study says, “We have a glimpse into the future in which we can detect premalignant lesions in the lung before they become tumors.”