DNA alterations could be precursors of lung cancer

The polymerase chain reaction has helped a team of US researchers to see the very earliest genetic changes that could mark the onset of the most common form of lung cancer. The results are published online in Nature Communications.

Lung adenocarcinoma

Source: Johns Hopkins Medicine

Understanding the precursors to lung cancer could improve the diagnosis and treatment of this form of cancer. While many lung lesions such as atypical adenomatous hyperplasia (AAH) will regress, some may act as a precursor to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and fully invasive adenocarcinoma. 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 five-year survival rate for people with adenocarcinoma is 15%, even with the most advanced chemotherapy, surgery and other treatments.

The researchers, from Johns Hopkins University, carried out targeted next-generation sequencing on multifocal AAHs and different zones of histologic progression within AISs and MIAs from DNA samples from lung tissue and blood taken from six patients who were having surgery for lung cancer.

By comparing the DNA of the premalignant lesions with DNA isolated from primary invasive cancer within each patient, the sequencing approach showed that in three of the patients, the same mutations were shared between the premalignant lesions and the tumour from the same patient.

The team found mutations associated with good and poor prognosis or responses to therapy were seen in different regions of the same tumour, highlighting the limitations of single biopsies commonly used to decide patients’ therapies. .

This finding of KRAS, TP53 and EGFR mutations is the first definitive link ever found between potential premalignant lesions and invasive tumours in the same lung, according to Evgeny Izumchenko of the Johns Hopkins University School of Medicine, and it suggests that those mutations may be the drivers of tumour progression.

PCR studies of blood plasma and sputum from two patients found alterations that were associated with early neoplasms in paired circulating DNA.

The team believes that these are among the very earliest premalignant genetic changes that mark the potential onset of the most common and deadliest form of disease, and these alterations occurred long before the lesions would acquire the ability to invade surrounding tissue and fulfil 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,” says Mariana Brait, PhD, of the Johns Hopkins University School of Medicine. “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.”

The researchers added 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,” says David Sidransky, MD of the Johns Hopkins University School of Medicine. “I’m not aware that circulating DNA from precancerous lesions this small has ever been identified before.”

It’s important to remember that the findings are preliminary and are from only a few patients. They may, however, lead to the use of DNA testing to detect precancerous changes at their earliest stages, as well as a better understanding of cancer molecular biology.

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