Plasma lncRNA expression profile as a prognostic tool in BRAF-mutant metastatic melanoma patients treated with BRAF inhibitor.

Tomasz Kolenda,Michał Michalak,Łukasz Galus,Katarzyna Lamperska,Katarzyna Kozak,Andrzej Mackiewicz,Sebastian Woźniak,Piotr Rutkowski,Anna Teresiak,Jacek Mackiewicz,Iwona Ługowska,Kacper Guglas,Marcel Ryś,Aleksandra Gos

doi:10.18632/oncotarget.26989

Abstract

Long non-coding RNAs (lncRNA) are dysregulated in many cancer types. Abnormal baseline levels of these lncRNAs display diagnostic and prognostic potential in cancer patients. The aim of this study was to evaluate the prognostic value of plasma lncRNAs in BRAF-mutant advanced melanoma patients treated with a BRAF inhibitor. Total RNA was isolated from plasma samples collected from 58 advanced BRAF-mutant melanoma patients and 15 healthy donors. The expression levels of 90 lncRNAs were estimated using the LncProfiler qPCR Array Kit (SBI) and LightCycler 96 (Roche). LncRNA expression levels correlated with responses to the BRAF inhibitor (vemurafenib) treatment. The patients were stratified into three groups based on their lncRNA levels with various lncRNA expressions (low, medium, and high). A Cox proportional hazards regression model was used to determine the lncRNAs that were significantly associated with both progression-free and overall survivals (PFS and OS, respectively) in patients receiving vemurafenib. The expression level of 12 lncRNAs was down-regulated, while five lncRNAs were up-regulated in melanoma patients compared to healthy donors. Kaplan-Meier analysis showed that upregulation or downregulation of 11 and 16 different lncRNAs were associated with longer median PFS and OS, respectively. Further analysis demonstrated that the baseline lncRNAs for IGF2AS, anti-Peg11, MEG3, Zeb2NAT are independent prognostic factors in BRAF-mutant advanced melanoma patients treated with vemurafenib. Evaluation of plasma lncRNAs expression level for advanced melanoma diagnosis and prognosis evaluation appears to be a safe and valuable method; however, this method requires further validation in larger cohorts and randomized trials.

Highlights

IntroductionThe introduction of immunotherapy and targeted therapy to standard treatment regimens has improved the prognosis of melanoma patients
The treatment landscape in melanoma is rapidly changing
The expressions of the following 12 Long non-coding RNAs (lncRNA) were significantly down-regulated in melanoma patients compared to healthy volunteers: (1) brain cytoplasmic (BC)200 (0.251 ± 0.081 versus 1.722 ± 0.792; p = 0.004); (2) E2F2 antisense (1.681 ± 0.543 versus 2.223 ± 0.864; p = 0.049); (3) H19 antisense (0.956 ± 0.165 versus 3.374 ± 1.047; p = 0.001); (4) homeobox transcript (HOTAIR) (8.537 ± 1.026 versus 1.334e+06 ± 9.450e+05; p = 0.039); (5) homeobox (HOX)A6as (0.173 ± 0.027 versus 12.02 ± 4.522; p = 0.001); (6) imprinted in Prader-Willi Syndrome (IPW) (0.058 ± 0.012 versus 0.125 ± 0.05; p = 0.026); (7)

Summary

Introduction

The introduction of immunotherapy and targeted therapy to standard treatment regimens has improved the prognosis of melanoma patients. Subsequent clinical studies showed that addition of a mitogen-activated protein kinase kinase (MEK) inhibitor to the BRAF inhibitor translates into further survival improvement [2,3,4,5,6,7]. Novel prognostic biomarkers have been identified in patients treated with targeted therapy (BRAF and MEK inhibitors) and immunotherapy (anti-programmed cell death protein [PD]1 and anti-cytotoxic T-lymphocyte–associated antigen [CTLA]4) [9,10,11]. Continuous research, including predictive biomarker identification, is required to guide physicians’ decision on whether targeted therapy or immunotherapy should be applied for the first-line treatment in BRAF mutant patients in order to improve their survival

Objectives

Methods

Results

Discussion

Conclusion