P1.07-027 13-Gene Signature of EMT Reveals Impact on Invasion and Metastasis of Neuroendocrine Carcinomas of the Lung: A Preliminary Study

Abstract

Metastasis are responsible for the death of 90% of patients with lung cancer, indicating the need to know the multiple signaling pathways involved. Neuroendocrine lung carcinomas (NELC) encompass a wide spectrum of tumors, from the low-grade typical carcinoid (TC) and atypical carcinoid (AC), to the high-grade large cell neuroendocrine carcinoma (LCNEC) and the small cell lung carcinoma (SCLC). Low-grade NELC are indolent, while high-grade NELC invade and metastasize rapidly. Biomarkers of NELC aggressiveness remain to be determined. Epithelial to mesenchymal transition (EMT) genes profile emerge promise as indicator of invasion and metastasis. Our aim was to evaluate: (1) EMT gene expression in NELC; (2) its relationship with the histologic subtypes and (3) its impact on behavior of the tumors. Patients with SCLC (n = 10), LCNEC (n=5), AC (n=2) and TC (n=7) were included, EMT gene expression was quantified with a quantitative real-time (RT)- PCR carried out on StepOnePlus™ Real-Time PCR System (Applied Biosystems), with RT2 Profiler PCR Array System for EMT (Qiagen, Dusseldorf, Germany). Associations of the gene signature and clinicopathological features, as well as prognostic factors were evaluated. A 13-gene signature (AHNAK, COL3A1, DSP, IL1RN, MSN, PDGFRB, SNAI1, SNAI3, TCF3, TGFβ1, TGFβ2, TGFβ3 and VIM) that was related to EMT was up-regulated in tumor-tissue from all NELC patients, mainly in those with high-grade NELC. An increased expression of DSP, TCF3 and TGFβ3 was found in SCLC compared to AC, TC and LCNEC, and associated with lymph nodes metastasis with statistical significance respectively for DSP (p=0.03 and 0.02), TCF3 (p=0.02) and marginal significance for TCF3 and TGFβ3 (p=0.08 and p=0.08). TCF3 was also associated with tobacco history (p=0.04). A significant correlation was found between enolase and IL1RN (p=0.03), chromogranin and TGFβ2 (p=0.04), synaptophysin and TGFβ1 and TGFβ2 respectively (p=0.04 and p=0.02). The EMT analysis identified genes involved in cell proliferation, motility, invasion and metastasis of NELC. We further inferred DSP, TCF3 and TGFβ3 as target against lung cancer metastasis and invasion, thus arising as promising therapeutic agent.