Gene Expression Analysis of Biphasic Pleural Mesothelioma: New Potential Diagnostic and Prognostic Markers.

Marco Lucchi,Franca Melfi,Rossella Bruno,Renato Franco,Antonio Chella,Claudia Distefano,Agnese Proietti,Anello Marcello Poma,Greta Alì,Gabriella Fontanini

doi:10.3390/diagnostics12030674

Abstract

Biphasic is the second most common histotype of pleural mesothelioma (PM). It shares epithelioid and sarcomatoid features and is challenging to diagnose. The aim of this study was to identify biphasic PM markers to improve subtyping and prognosis definition. The expression levels of 117 cancer genes, evaluated using the nanoString system, were compared between the three major histotypes (epithelioid, sarcomatoid, and biphasic), and expression differences within biphasic PM were evaluated in relation to the percentage of epithelioid components. Biphasic PM overexpressed CTNNA1 and TIMP3 in comparison to sarcomatoid, and COL16A1 and SDC1 in comparison to epithelioid PM. CFB, MSLN, CLDN15, SERPINE1, and PAK4 were deregulated among all histotypes, leading to the hypothesis of a gradual expression from epithelioid to sarcomatoid PM. According to gene expression, biphasic PM samples were divided in two clusters with a significant difference in the epithelioid component. ADCY4, COL1A1, and COL4A2 were overexpressed in the biphasic group with a low percentage of epithelioid component. Survival analysis using TCGA data showed that high COL1A1 and COL4A2 expression levels correlate with poor survival in PM patients. Herein, we identified markers with the potential to improve diagnosis and prognostic stratification of biphasic PM, which is still an orphan tumor.

Highlights

Pleural mesothelioma (PM) is a rare and highly aggressive tumor, mostly associated with asbestos exposure [1,2]
We mainly focused on biphasic pleural mesothelioma (PM), in order to underline differences with epithelioid and sarcomatoid PM and to investigate new potential prognostic biomarkers correlated with the amount of epithelioid component
All tumor samples were formalin-fixed and paraffin-embedded (FFPE); histological diagnosis and pathological features were independently reviewed by two pathologists (GA and GF) according to the World Health Organization (WHO) 5th edition criteria [5] (Figure 1)

Summary

Introduction

Pleural mesothelioma (PM) is a rare and highly aggressive tumor, mostly associated with asbestos exposure [1,2]. PM is characterized by a long latency period (10–30 years) from asbestos exposure to the clinical onset of disease, with a median overall survival ranging from 12–18 months and a 5-year survival rate of about 5% [3,4]. According to the 5th World Health Organization (WHO) Thoracic Tumors classification, diffuse PM includes three major histotypes: epithelioid (70–80% of cases), sarcomatoid (10%), and biphasic or mixed (10–20%) [5]. The reported median overall survival rate for epithelioid, biphasic and sarcomatoid PM is 19, 12, and 4 months, respectively [6,7]. A PM is classified as biphasic if both epithelioid and sarcomatoid components are present, with each comprising at least 10% of the tumor, and the proportion of sarcomatoid component is the major prognostic indicator and treatment driver [8,9]. Chirieac and collaborators compared pre-surgery biopsies and surgical resection specimens from 759 PM patients: 112 patients (19%), initially diagnosed as epithelioid, were reclassified as biphasic after surgical resection; 15 (11%) and 4 (3%) cases initially diagnosed as biphasic were reclassified as epithelioid and sarcomatoid, respectively; 7 (19%) cases initially diagnosed as sarcomatoid were reclassified as biphasic [10]

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Results