Telomere Status of Advanced Non-Small-Cell Lung Cancer Offers a Novel Promising Prognostic and Predictive Biomarker

SIMPLE SUMMARY: Short, dysfunctional telomeres represent the genetic biomarkers of cancer. Studies in early-stage non-small-cell lung cancer (NSCLC) have shown that telomere length and telomerase levels are correlated with survival. In patients with advanced NSCLC, telomere status has not yet been investigated, and its clinical significance remains unknown. We studied telomere length and the expression of telomerase and shelterin genes in a cohort of 79 patients with advanced NSCLC, and evaluated these parameters as potential prognostic and predictive factors. Telomere shortening, high levels of telomerase and aberrant expression of shelterin genes TRF2, RAP1 and TIN2 were significantly correlated with shorter survival. Furthermore, a worse response to immunotherapy was observed in patients with shorter telomeres. The determination of telomere parameters in advanced NSCLC could be useful for individualized treatment decisions. ABSTRACT: Telomere length appears to correlate with survival in early non-small-cell lung cancer (NSCLC), but the prognostic impact of telomere status in advanced NSCLC remains undetermined. Our purpose was to evaluate telomere parameters as prognostic and predictive biomarkers in advanced NSCLC. In 79 biopsies obtained before treatment, we analyzed the telomere length and expression of TERT and shelterin complex genes (TRF1, TRF2, POT1, TPP1, RAP1, and TIN2), using quantitative PCR. Non-responders to first-line chemotherapy were characterized by shorter telomeres and low RAP1 expression (p = 0.0035 and p = 0.0069), and tended to show higher TERT levels (p = 0.058). In multivariate analysis, short telomeres were associated with reduced event-free (EFS, p = 0.0023) and overall survival (OS, p = 0.00041). TERT and TRF2 overexpression correlated with poor EFS (p = 0.0069 and p = 0.00041) and OS (p = 0.0051 and p = 0.007). Low RAP1 and TIN2 expression-levels were linked to reduced EFS (p = 0.00032 and p = 0.0069) and OS (p = 0.000051 and p = 0.02). Short telomeres were also associated with decreased survival after nivolumab therapy (p = 0.097). Evaluation of telomere status in advanced NSCLC emerges as a useful biomarker that allows for the selection of patient groups with different clinical evolutions, to establish personalized treatment.