| Summary: | 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 <i>CTNNA1</i> and <i>TIMP3</i> in comparison to sarcomatoid, and <i>COL16A1</i> and <i>SDC1</i> in comparison to epithelioid PM. <i>CFB</i>, <i>MSLN</i>, <i>CLDN15</i>, <i>SERPINE1</i>, and <i>PAK4</i> 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. <i>ADCY4</i>, <i>COL1A1</i>, and <i>COL4A2</i> were overexpressed in the biphasic group with a low percentage of epithelioid component. Survival analysis using TCGA data showed that high <i>COL1A1</i> and <i>COL4A2</i> 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.
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