Unproductive Effects of ALK Gene Amplification and Copy Number Gain in Non-Small-Cell Lung Cancer. ALK Gene Amplification and Copy Gain in NSCLC.

Federica Zito Marino,Alessandro Morabito,Pietro Micheli,Gabriella Aquino,Rossella De Cecio,Danilo Rocco,Renato Franco,Stefano Ferrero,Maria Carolina Micheli,Alessandro Palleschi,Gaetano Rocco,Antonio Giordano,Gerardo Botti,Rosario Salvi,Gabriella Gaudioso

doi:10.3390/ijms21144927

Abstract

Background: The Anaplastic Lymphoma Kinase (ALK) gene is known to be affected by several genetic alterations, such as rearrangement, amplification and point mutation. The main goal of this study was to comprehensively analyze ALK amplification (ALK-A) and ALK gene copy number gain (ALK-CNG) in a large cohort of non-small-cell lung cancer (NSCLC) patients in order to evaluate the effects on mRNA and protein expression. Methods: ALK locus number status was evaluated in 578 NSCLC cases by fluorescence in situ hybridization (FISH). In addition, ALK immunohistochemistry and ALK mRNA in situ hybridization were performed. Results: Out of 578 cases, 17 cases showed ALK-A. In addition, 14 cases presented ALK-CNG and 72 cases presented chromosome 2 polyploidy. None of those carrying ALK-A and -CNG showed either ALK immunohistochemical expression or ALK mRNA expression through in situ hybridization. We observed a high frequency of extra copies of the ALK gene. Conclusions: Our findings demonstrated that ALK-A is not involved in mRNA production and consequently is not involved in protein production; these findings support the hypothesis that ALK-A might not play a role in the pathogenesis of NSCLC, underlining the absence of a specific clinical application.

Highlights

Anaplastic lymphoma kinase (ALK) is a transmembrane tyrosine kinase receptor
We examined Anaplastic Lymphoma Kinase (ALK) mRNA expression in cases of non-small-cell lung cancer (NSCLC) carrying ALK amplification (ALK-A) in order to evaluate the status of gene transcription in ALK-A and ALK gene copy number gain (ALK-CNG) cases
fluorescence in situ hybridization (FISH) analysis of chromosome 2 centromeric probes is indispensable in defining true ALK copy number gain status and amplification compared to chromosome 2 polysomy

Summary

Introduction

Anaplastic lymphoma kinase (ALK) is a transmembrane tyrosine kinase receptor. During embryogenesis, ALK is expressed in the nervous system, but its expression decreases after birth [1]. In anaplastic large cell lymphoma (ALCL), ALK was originally characterized as a nucleophosmin fusion partner [2]. ALK rearrangement (ALK-R) has been reported in 3–7% of all non-small-cell lung cancers (NSCLCs). The Anaplastic Lymphoma Kinase (ALK) gene is known to be affected by several genetic alterations, such as rearrangement, amplification and point mutation. The main goal of this study was to comprehensively analyze ALK amplification (ALK-A) and ALK gene copy number gain (ALK-CNG) in a large cohort of non-small-cell lung cancer (NSCLC) patients in order to evaluate the effects on mRNA and protein expression. 14 cases presented ALK-CNG and 72 cases presented chromosome 2 polyploidy. None of those carrying ALK-A and -CNG showed either ALK immunohistochemical expression or ALK mRNA expression through in situ hybridization. Conclusions: Our findings demonstrated that ALK-A is not involved in mRNA production and is not involved in protein production; these findings support the hypothesis that ALK-A might not play a role in the pathogenesis of NSCLC, underlining the absence of a specific clinical application

Objectives

Methods

Conclusion