{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:26:08Z","timestamp":1772252768403,"version":"3.50.1"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T00:00:00Z","timestamp":1618790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms22084217","type":"journal-article","created":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T11:21:38Z","timestamp":1618831298000},"page":"4217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["MET Exon 14 Skipping: A Case Study for the Detection of Genetic Variants in Cancer Driver Genes by Deep Learning"],"prefix":"10.3390","volume":"22","author":[{"given":"Vladimir","family":"Nosi","sequence":"first","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandr\u00ec","family":"Luca","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa","family":"Milan","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maddalena","family":"Arigoni","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Benvenuti","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Cacchiarelli","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcella","family":"Cesana","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Riccardo","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucio","family":"Di Filippo","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3143-3330","authenticated-orcid":false,"given":"Francesca","family":"Cordero","sequence":"additional","affiliation":[{"name":"Department of Computer Sciences, University of Torino, 10149 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Beccuti","sequence":"additional","affiliation":[{"name":"Department of Computer Sciences, University of Torino, 10149 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo M.","family":"Comoglio","sequence":"additional","affiliation":[{"name":"IFOM-FIRC Institute of Molecular Oncology, 20139 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2848-628X","authenticated-orcid":false,"given":"Raffaele A.","family":"Calogero","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/S0168-9525(00)02176-4","article-title":"Alternative splicing: Increasing diversity in the proteomic world","volume":"17","author":"Graveley","year":"2001","journal-title":"Trends Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1038\/ng.259","article-title":"Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing","volume":"40","author":"Pan","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.bbadis.2008.09.017","article-title":"Alternative splicing and disease","volume":"1792","author":"Tazi","year":"2009","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"188","DOI":"10.12688\/f1000research.2-188.v1","article-title":"Thousands of exon skipping events differentiate among splicing patterns in sixteen human tissues","volume":"2","author":"Florea","year":"2013","journal-title":"F1000Research"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.csbj.2020.12.009","article-title":"Alternative splicing: Human disease and quantitative analysis from high-throughput sequencing","volume":"19","author":"Jiang","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_6","first-page":"D896","article-title":"ExonSkipDB: Functional annotation of exon skipping event in human","volume":"48","author":"Kim","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/s41568-018-0060-1","article-title":"The COSMIC Cancer Gene Census: Describing genetic dysfunction across all human cancers","volume":"18","author":"Sondka","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1158\/2159-8290.CD-15-0285","article-title":"Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors","volume":"5","author":"Frampton","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1158\/2159-8290.CD-15-0769","article-title":"MET Receptor Juxtamembrane Exon 14 Alternative Spliced Variant: Novel Cancer Genomic Predictive Biomarker","volume":"5","author":"Ma","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.21037\/jtd.2020.04.21","article-title":"Frequency of MET exon 14 skipping mutations in non-small cell lung cancer according to technical approach in routine diagnosis: Results from a real-life cohort of 2369 patients","volume":"12","author":"Champagnac","year":"2020","journal-title":"J. Thorac. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1056\/NEJMoa2004407","article-title":"Tepotinib in Non\u2013Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations","volume":"383","author":"Paik","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1200\/JCO.2015.63.4600","article-title":"MET Exon 14 Mutations in Non\u2013Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression","volume":"34","author":"Awad","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1016\/j.jtho.2016.05.005","article-title":"cMET Exon 14 Skipping: From the Structure to the Clinic","volume":"11","author":"Giovannetti","year":"2016","journal-title":"J. Thorac. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Marczyk, M., Fu, C., Lau, R., Du, L., Trevarton, A.J., Sinn, B., Gould, R.E., Pusztai, L., Hatzis, C., and Symmans, W.F. (2019). The impact of RNA extraction method on accurate RNA sequencing from formalin-fixed paraf-fin-embedded tissues. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6363-0"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.lungcan.2019.11.010","article-title":"Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer","volume":"140","author":"Pruis","year":"2020","journal-title":"Lung Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.jtho.2018.12.020","article-title":"DNA-Based versus RNA-Based Detection of MET Exon 14 Skipping Events in Lung Cancer","volume":"14","author":"Davies","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12864-018-5350-1","article-title":"Discerning novel splice junctions derived from RNA-seq alignment: A deep learning approach","volume":"19","author":"Zhang","year":"2018","journal-title":"BMC Genom."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Du, X., Hu, C., Yao, Y., Sun, S., and Zhang, Y. (2017). Analysis and Prediction of Exon Skipping Events from RNA-Seq with Sequence Information Using Rotation Forest. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122691"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4180","DOI":"10.1093\/bioinformatics\/bty497","article-title":"SpliceRover: Interpretable convolutional neural networks for improved splice site prediction","volume":"34","author":"Zuallaert","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting Splicing from Primary Sequence with Deep Learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12859-019-3039-3","article-title":"A classification model for lncRNA and mRNA based on k-mers and a convolutional neural network","volume":"20","author":"Wen","year":"2019","journal-title":"BMC Bioinform."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nbt.1754","article-title":"Integrative genomics viewer","volume":"29","author":"Robinson","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2838","DOI":"10.1002\/ijc.31831","article-title":"The expression of LINE1-MET chimeric transcript identifies a subgroup of aggressive breast cancers","volume":"143","author":"Miglio","year":"2018","journal-title":"Int. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"Altschul","year":"1990","journal-title":"J. Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41540-020-00162-6","article-title":"Sparsely-connected autoencoder (SCA) for single cell RNAseq data mining","volume":"7","author":"Alessandri","year":"2021","journal-title":"NPJ Syst. Biol. Appl."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ye, X., and Ho, J.W.K. (2019). Ultrafast clustering of single-cell flow cytometry data using FlowGrid. BMC Syst. Biol., 13.","DOI":"10.1186\/s12918-019-0690-2"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/s41592-018-0033-z","article-title":"SAVER: Gene expression recovery for single-cell RNA sequencing","volume":"15","author":"Huang","year":"2018","journal-title":"Nat. Methods"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11864-020-0723-5","article-title":"Management of Non-small Cell Lung Cancer Patients with MET Exon 14 Skipping Mutations","volume":"21","author":"Huang","year":"2020","journal-title":"Curr. Treat. Options Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1038\/onc.2016.283","article-title":"Dual MET\/EGFR therapy leads to complete response and resistance prevention in a MET-amplified gas-troesophageal xenopatient cohort","volume":"36","author":"Apicella","year":"2017","journal-title":"Oncogene"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e35","DOI":"10.1016\/j.clon.2016.01.009","article-title":"Targeting the MET Pathway in Gastric and Oesophageal Cancers: Refining the Optimal Approach","volume":"28","author":"Lee","year":"2016","journal-title":"Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"28211","DOI":"10.18632\/oncotarget.4721","article-title":"Gastrointestinal malignancies harbor actionable MET exon 14 deletions","volume":"6","author":"Lee","year":"2015","journal-title":"Oncotarget"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1136\/gutjnl-2012-304219","article-title":"Hypomethylation of long interspersed nuclear element-1 (LINE-1) leads to activation of proto-oncogenes in human colorectal cancer metastasis","volume":"63","author":"Hur","year":"2014","journal-title":"Gut"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1158\/0008-5472.CAN-06-3495","article-title":"Lung Cancer Cell Lines Harboring MET Gene Amplification Are Dependent on Met for Growth and Survival","volume":"67","author":"Lutterbach","year":"2007","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1016\/j.bbrc.2010.03.120","article-title":"Gastric cancer cell line Hs746T harbors a splice site mutation of c-Met causing juxtamembrane domain deletion","volume":"394","author":"Asaoka","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e525","DOI":"10.1016\/j.ijrobp.2012.06.025","article-title":"Higher Levels of c-Met Expression and Phosphorylation Identify Cell Lines With Increased Sensitivity to AMG-458, a Novel Selective c-Met Inhibitor With Radiosensitizing Effects","volume":"84","author":"Li","year":"2012","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1158\/0008-5472.CAN-05-2749","article-title":"Somatic Mutations Lead to an Oncogenic Deletion of Met in Lung Cancer","volume":"66","author":"Seshagiri","year":"2006","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2105-12-333","article-title":"Efficient counting of k-mers in DNA sequences using a bloom filter","volume":"12","author":"Melsted","year":"2011","journal-title":"BMC Bioinform."}],"updated-by":[{"DOI":"10.3390\/ijms27020986","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T00:00:00Z","timestamp":1618790400000}}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/4217\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T11:36:21Z","timestamp":1768822581000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/4217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,19]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22084217"],"URL":"https:\/\/doi.org\/10.3390\/ijms22084217","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202103.0676.v1","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,19]]}}}