Helicase-like transcription factor expression is associated with a poor prognosis in Non-Small-Cell Lung Cancer (NSCLC)

Alexandra Belayew,Roya Navab,Arsène Burny,Céline Mascaux,Ming-Sound Tsao,Melania Pintilie,Ludovic Dhont,Frances Shepherd,Ethan Kaufman,Shirley Tam

doi:10.1186/s12885-018-4215-y

Abstract

BackgroundThe relapse rate in early stage non-small cell lung cancer (NSCLC) after surgical resection is high. Prognostic biomarkers may help identify patients who may benefit from additional therapy. The Helicase-like Transcription Factor (HLTF) is a tumor suppressor, altered in cancer either by gene hypermethylation or mRNA alternative splicing. This study assessed the expression and the clinical relevance of wild-type (WT) and variant forms of HLTF RNAs in NSCLC.MethodsWe analyzed online databases (TCGA, COSMIC) for HLTF alterations in NSCLC and assessed WT and spliced HLTF mRNAs expression by RT-ddPCR in 39 lung cancer cell lines and 171 patients with resected stage I-II NSCLC.ResultsIn silico analyses identified HLTF gene alterations more frequently in lung squamous cell carcinoma than in adenocarcinoma. In cell lines and in patients, WT and I21R HLTF mRNAs were detected, but the latter at lower level. The subgroup of 25 patients presenting a combined low WT HLTF expression and a high I21R HLTF expression had a significantly worse disease-free survival than the other 146 patients in univariate (HR 1.96, CI 1.17–3.30; p = 0.011) and multivariate analyses (HR 1.98, CI 1.15–3.40; p = 0.014).ConclusionA low WT HLTF expression with a high I21R HLTF expression is associated with a poor DFS.

Highlights

The relapse rate in early stage non-small cell lung cancer (NSCLC) after surgical resection is high
While a high expression of Helicase-like Transcription Factor (HLTF) was more frequently reported in squamous cell carcinoma (SCC) than in ADC (28.6% vs 7.5%, p < 0.0001), a negative correlation between HLTF expression and its methylation status was found in both SCC (Pearson: − 0.475 and Spearman: − 0.484; Fig. 1) and ADC (Pearson: − 0.473 and Spearman: − 0.420; Fig. 1)
The present study showed that in a cohort of 171 patients, the combination of low expression of WT HLTF transcript and high expression of intron 21 retention (I21R) HLTF transcript was associated with poor prognosis in early stage NSCLC

Summary

Introduction

The relapse rate in early stage non-small cell lung cancer (NSCLC) after surgical resection is high. 16% of patients affected with Non-small cell lung cancer (NSCLC), which is the most common subtype, are alive 5 years after diagnosis, and this number has hardly improved over several decades [1]. One reason for this poor prognosis is that only 15% of lung cancers are diagnosed at an early stage. An effort to identify more robust prognostic and predictive biomarkers is needed [5]

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