Monitoring HOTTIP levels on extracellular vesicles for predicting recurrence in surgical non-small cell lung cancer patients

Ramón María Marrades,Alfons Navarro,Coralí Cros-Font,Tania Díaz,Bing Han,Laureano Molins,Yangyi He,Jordi Canals,David Sánchez,Jorge Moisés,Melissa Acosta-Plasencia,Nuria Viñolas,Mariano Monzo,Daniel Martinez,Marc Boada

doi:10.1016/j.tranon.2021.101144

Abstract

In resected non-small cell lung cancer (NSCLC), postsurgical recurrence is the major factor affecting long-term survival. The identification of biomarkers in extracellular vesicles (EV) obtained from serial blood samples after surgery could enhance early detection of relapse and improve NSCLC outcome. Since EV cargo contains long non-coding RNAs (lncRNAs), we aimed to analyze whether the oncogenic lncRNA HOTTIP, which higher expression in tumor tissue was related to worse outcome in NSCLC, could be detected in EV from NSCLC patients and serve as recurrence biomarker. After purification of EVs by ultracentrifugation in 52 serial samples from 18 NSCLC patients, RNA was isolated and HOTTIP was quantified by Real time PCR. We observed that patients that relapsed after surgery displayed increased postsurgical EV HOTTIP levels in comparison with presurgical levels. In the relapsed patients with several samples available between surgery and relapse, we observed an increment in the EV HOTTIP levels when approaching to relapse, which indicated its potential utility for monitoring disease recurrence. When we focused in EV HOTTIP levels in the first post-surgical sample, we observed that the detection of an increment of the expression levels in comparison to presurgical sample, predicted recurrence with high sensitivity (85.7%) and specificity (90.9%) and that patients had shorter time to relapse and shorter overall survival. In conclusion, our pilot study showed that EV HOTTIP is a potential biomarker for monitoring disease recurrence after surgery in NSCLC.

Highlights

The GLOBOCAN2020 reported that lung cancer accounts for 11.4% of total cancer diagnoses and it is still the leading cause of death due to oncological disease in both sexes [1]
Since extracellular vesicles (EV) cargo contains long non-coding RNAs, we aimed to analyze whether the oncogenic lncRNA HOTTIP, which higher expression in tumor tissue was related to worse outcome in non-small cell lung cancer (NSCLC), could be detected in EV from NSCLC patients and serve as recurrence biomarker
When we focused in EV HOTTIP levels in the first post-surgical sample, we observed that the detection of an increment of the expression levels in comparison to presurgical sample, predicted recurrence with high sensitivity (85.7%) and specificity (90.9%) and that patients had shorter time to relapse and shorter overall survival

Summary

Introduction

The GLOBOCAN2020 reported that lung cancer accounts for 11.4% of total cancer diagnoses and it is still the leading cause of death due to oncological disease in both sexes [1]. Resected patients are considered disease-free after surgery, its prognosis is still very unfavorable with a 5-year survival of 60–80% [3,4,5]due to high relapse rates of around 40% [6]. It is crucial to find prognostic biomarkers to detect pa tients at high risk of relapse after surgery. Prognostic biomarkers to classify patients into risk groups have been evaluated by means of tumor tissue analysis [7] and by analyzing the patient’s blood, the so-called liquid biopsy [8,9] that includes between others the study of circulating tumor cells, the circulating free DNA/RNA or more recently the study of extracellular vesicles (EV) [10]

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