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Despite advances in diagnostics and therapy of non-small cell lung cancer (NSCLC), the problem of prognosis and prevention of tumor progression is still highly important. Even if NSCLC is diagnosed in the early stages, almost a quarter of patients develop relapse; most of them die from recurrent disease. A large number of different markers have been proposed to predict the risk of NSCLC progression; however, none of them are used in clinical practice. It is obvious that this situation is related to the economic and methodological complexity of the proposed markers and/or their insufficient efficiency due to a lack of effective study models and tumor heterogeneity. Another reason may be that potential markers are developed for NSCLC progression in general, which is represented by at least four pathogenetically-distinct processes: synchronous lymph node metastasis, local, regional, and distant recurrence. In this review, we summarize data from published literature on clinicopathological, genetic, and molecular factors associated with different types of NSCLC progression and emphasize challenges and approaches to developing prognostic factors. In conclusion, we highlight the importance of further studies to reveal molecular mechanisms of NSCLC progression and the need for differential analysis of markers of local, regional, and distant recurrences for disease prognosis.

BackgroundThe study assessed the possibility of dividing patients into groups based on the assessment of morphological changes in the epithelium of small-caliber bronchi located near the primary tumor in order to predict high and low risks of distant metastasis of non-small cell lung cancer.MethodsIn 171 patients with non-small cell lung cancer (T1-4N0-3M0) in small-caliber bronchi taken at a distance of 3–5 cm from the tumor, various variants of morphological changes in the bronchial epithelium (basal cell hyperplasia (BCH), squamous cell metaplasia (SM), and dysplasia (D)) were assessed. Long-term results of treatment, namely, distant metastasis, were assessed after 2 and 5 years.ResultsDuring the follow-up period, distant metastases were found in 35.1% (60/171) of patients. Most often, they were observed in patients of the high-risk group: BCH+SM−D− (51.6%, 40/95) and BCH−SM+D+ (54.4%, 6/11). Less often, distant metastases were observed in low-risk group patients: BCH+SM+D− (6.7%, 3/45) and BCH−SM−D− (10.0%, 2/20). Tumor size, grade, and stage were significant predictors of metastasis only in the high-risk group. The 5-year metastasis-free survival was better in the low-risk group of distant metastases.ConclusionsIsolated BCH or dysplasia in small bronchi distant from foci of tumor is associated with a high-risk distant metastasis and less 5-year metastasis-free survival.

Along with other malignant diseases, lung cancer arises from the precancerous lung tissue state. Aberrant DNA methylation (hypermethylation of certain genes and hypomethylation of retrotransposons) is known as one of the driving forces of malignant cell transformation. Epigenetic changes were shown to be detectable in DNA, circulating in the blood (cirDNA) of cancer patients, indicating the possibility to use them as cancer markers. The current study is the first to compare the Long interspersed nuclear element-1 (LINE-1) methylation level in the blood from lung cancer patients before treatment versus different control groups as healthy subjects, patients with bronchitis and patients with chronic obstructive pulmonary disease (COPD). The concentration of LINE-1 methylated fragments, region 1 (LINE-1 methylated, LINE-1-met) was estimated by quantitative methyl-specific PCR. The total concentration of the circulating LINE-1 copies was measured by qPCR specific for LINE-1 region 2, which was selected due to its CpG methylation–independent sequence (LINE-1-Ind). Both LINE-1 methylation level and LINE-1 methylation index (LINE-1-met/LINE-1-Ind ratio) was decreased in lung cancer patients compared with the joint control group (healthy subjects + patients with bronchitis + COPD patients) (Mann–Whitney U-test, P = 0.016). We also found that the tendency of LINE-1 methylation index decreases in the cirDNA from lung cancer patients versus COPD patients (Mann–Whitney U-test, P = 0.07). Our data indicate that the quantitative analysis of the LINE-1 methylation level in the cirDNA is valuable for discrimination of lung cancer patients from patients with chronic inflammatory lung diseases.