True 3q Chromosomal Amplification in Squamous Cell Lung Carcinoma by FISH and aCGH Molecular Analysis: Impact on Targeted Drugs

Matteo Brunelli,Francesco Massari,Antonio Santo,Alessia Nottegar,Ioana Borze,Albino Eccher,Guido Martignoni,Sara Cingarlini,Serena Pedron,Francesco Calabrò,Stefano Gobbo,Claudia Parolini,Giampaolo Tortora,Eliana Gilioli,Luca Tondulli,Francesca Simionato,Emilio Bria,Antonio Iannucci,Marco Chilosi,Anna Caliò,Sakari Knuutila

doi:10.1371/journal.pone.0049689

Matteo Brunelli, Francesco Massari + Show 19 more

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https://doi.org/10.1371/journal.pone.0049689

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Abstract

Squamous lung carcinoma lacks specific “ad hoc” therapies. Amplification of chromosome 3q is the most common genomic aberration and this region harbours genes having role as novel targets for therapeutics. There is no standard definition on how to score and report 3q amplification. False versus true 3q chromosomal amplification in squamous cell lung carcinoma may have tremendous impact on trials involving drugs which target DNA zones mapping on 3q. Forty squamous lung carcinomas were analyzed by FISH to assess chromosome 3q amplification. aCGH was performed as gold-standard to avoid false positive amplifications. Three clustered patterns of fluorescent signals were observed. Eight cases out of 40 (20%) showed ≥8 3q signals. Twenty out of 40 (50%) showed from 3 to 7 signals. The remaining showed two fluorescent signals (30%). When corrected by whole chromosome 3 signals, only cases with ≥8 signals maintained a LSI 3q/CEP3 ratio >2. Only the cases showing 3q amplification by aCGH (+3q25.3−3q27.3) showed ≥8 fluorescent signals at FISH evidencing a 3q/3 ratio >2. The remaining cases showed flat genomic portrait at aCGH on chromosome 3. We concluded that: 1) absolute copy number of 3q chromosomal region may harbour false positive interpretation of 3q amplification in squamous cell carcinoma; 2) a case results truly “amplified for chromosome 3q” when showing ≥8 fluorescent 3q signals; 3) trials involving drugs targeting loci on chromosome 3q in squamous lung carcinoma therapy have to consider false versus true 3q chromosomal amplification.

Highlights

IntroductionUnlike adenocarcinomas of the lung among which the increasing genomic characterization has simultaneously led to increase their biological portrait [1,2,3], squamous cell carcinoma remains a disease bereft of a molecular targeted profile
Squamous cell cancer accounts for about thirty per cent of lung cancer [1]
Unlike adenocarcinomas of the lung among which the increasing genomic characterization has simultaneously led to increase their biological portrait [1,2,3], squamous cell carcinoma remains a disease bereft of a molecular targeted profile. This leads to consider the need for studies that enhance the molecular changes that, like EGFR, K-ras and ALK genes for lung adenocarcinoma, at prognostic and/or predictive levels may give chances for an effective therapeutic response in these patients [4]

Summary

Introduction

Unlike adenocarcinomas of the lung among which the increasing genomic characterization has simultaneously led to increase their biological portrait [1,2,3], squamous cell carcinoma remains a disease bereft of a molecular targeted profile. This leads to consider the need for studies that enhance the molecular changes that, like EGFR, K-ras and ALK genes for lung adenocarcinoma, at prognostic and/or predictive levels may give chances for an effective therapeutic response in these patients [4]. Squamous lung carcinoma remains a neoplastic tissue orphan of specific ‘‘ad hoc’’ therapies, there is a need to identify new molecular and cytogenetic biomarkers usefull in selecting patients for new drugs and in designing new clinical trials [9,10]

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