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MET Exon 14 Skipping: A Case Study for the Detection of Genetic Variants in Cancer Driver Genes by Deep Learning

Authors :
Maddalena Arigoni
Paolo M. Comoglio
Francesca Cordero
Vladimir Nosi
Alessandrì Luca
Silvia Benvenuti
Sara Riccardo
Raffaele A. Calogero
Marcella Cesana
Marco Beccuti
Davide Cacchiarelli
Lucio Di Filippo
Melissa Milan
Nosi, V.
Luca, A.
Milan, M.
Arigoni, M.
Benvenuti, S.
Cacchiarelli, D.
Cesana, M.
Riccardo, S.
Filippo, L. D.
Cordero, F.
Beccuti, M.
Comoglio, P. M.
Calogero, R. A.
Source :
International Journal of Molecular Sciences, Volume 22, Issue 8, International Journal of Molecular Sciences, Vol 22, Iss 4217, p 4217 (2021)
Publication Year :
2021

Abstract

Background: Disruption of alternative splicing (AS) is frequently observed in cancer and might represent an important signature for tumor progression and therapy. Exon skipping (ES) represents one of the most frequent AS events, and in non-small cell lung cancer (NSCLC) MET exon 14 skipping was shown to be targetable. Methods: We constructed neural networks (NN/CNN) specifically designed to detect MET exon 14 skipping events using RNAseq data. Furthermore, for discovery purposes we also developed a sparsely connected autoencoder to identify uncharacterized MET isoforms. Results: The neural networks had a Met exon 14 skipping detection rate greater than 94% when tested on a manually curated set of 690 TCGA bronchus and lung samples. When globally applied to 2605 TCGA samples, we observed that the majority of false positives was characterized by a blurry coverage of exon 14, but interestingly they share a common coverage peak in the second intron and we speculate that this event could be the transcription signature of a LINE1 (Long Interspersed Nuclear Element 1)-MET (Mesenchymal Epithelial Transition receptor tyrosine kinase) fusion. Conclusions: Taken together, our results indicate that neural networks can be an effective tool to provide a quick classification of pathological transcription events, and sparsely connected autoencoders could represent the basis for the development of an effective discovery tool.

Details

ISSN :
14220067
Volume :
22
Issue :
8
Database :
OpenAIRE
Journal :
International journal of molecular sciences
Accession number :
edsair.doi.dedup.....060ff7d685743f48be64a6cd274f3926