{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T13:00:54Z","timestamp":1765976454079,"version":"3.41.2"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>This paper aims to identify alternative RNA splicing landscape and its prognostic value in adrenocortical carcinoma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The alternative splicing events data with corresponding clinical information data of 79 ACC patients were obtained from the Cancer Genome Atlas and SpliceSeq package. Prognosis-associated AS events by using univariate Cox regression analysis were selected. Gene functional enrichment analysis demonstrated the potential pathways enriched by survival-associated AS. Prognosis-related splicing events were submitted to develop moderate predictors using Lasso regression model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>One thousand five survival-associated alternative splicing events were identified. The prognostic genes included <jats:italic>ATXN2L, MEIS1<\/jats:italic>, <jats:italic>IKBKB<\/jats:italic>, <jats:italic>COX4I1<\/jats:italic>. Functional enrichment analysis suggested that prognostic splicing events are associated with Wnt signaling pathway. A prediction model including 12 alternative splicing events was constructed by Lasso regression using train set. ROC analysis showed good performance of the prediction model in test set. Then, a nomogram integrating the clinical-pathological factors and riskscore was constructed for predicting 1\u2010 and 3\u2010year survival rate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data provide a comprehensive bioinformatics analysis of AS events in ACC, providing biomarkers for disease progression and a potentially rich source of novel therapeutic targets.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2021.538364","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T07:03:09Z","timestamp":1615532589000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Prognostic Alternative mRNA Splicing in Adrenocortical Carcinoma"],"prefix":"10.3389","volume":"12","author":[{"given":"Weiwei","family":"Liang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangfang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.08.012","article-title":"The Functional Impact of Alternative Splicing in Cancer","volume":"20","author":"Climente-Gonzalez","year":"2017","journal-title":"Cell Rep"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.01.029","article-title":"Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing","volume":"164","author":"Yang","year":"2016","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.gde.2017.10.001","article-title":"The role of alternative splicing in cancer drug resistance","volume":"48","author":"Siegfried","year":"2018","journal-title":"Curr Opin Genet Dev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2013.02.034","article-title":"Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993","volume":"49","author":"Kerkhofs","year":"2013","journal-title":"Eur J Cancer (Oxford Engl 1990)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-0706","article-title":"Prognostic parameters of metastatic adrenocortical carcinoma","volume":"92","author":"Assie","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-005-0329-x","article-title":"Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress","volume":"30","author":"Kebebew","year":"2006","journal-title":"World J Surg"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.24030","article-title":"Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification","volume":"115","author":"Fassnacht","year":"2009","journal-title":"Cancer"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.23886","article-title":"Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors","volume":"113","author":"Bilimoria","year":"2008","journal-title":"Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-2856","article-title":"Adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with adrenocortical carcinoma","volume":"99","author":"Else","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-13-0519","article-title":"Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center","volume":"169","author":"Ayala-Ramirez","year":"2013","journal-title":"Eur J Endocrinol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-18-0027","article-title":"MANAGEMENT OF ENDOCRINE DISEASE: Adrenocortical carcinoma: differentiating the good from the poor prognosis tumors","volume":"178","author":"Jouinot","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1288","article-title":"TCGASpliceSeq a compendium of alternative mRNA splicing in cancer","volume":"44","author":"Ryan","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts452","article-title":"SpliceSeq: a resource for analysis and visualization of RNA-Seq data on alternative splicing and its functional impacts","volume":"28","author":"Ryan","year":"2012","journal-title":"Bioinformatics"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx364","article-title":"UpSetR: an R package for the visualization of intersecting sets and their properties","volume":"33","author":"Conway","year":"2017","journal-title":"Bioinformatics"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4097\/kja.19183","article-title":"Survival analysis: part II - applied clinical data analysis","volume":"72","author":"Lee","year":"2019","journal-title":"Korean J Anesthesiol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v033.i01","article-title":"Regularization Paths for Generalized Linear Models via Coordinate Descent","volume":"33","author":"Friedman","year":"2010","journal-title":"J Stat Softw"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S147717","article-title":"Identification and validation of potential prognostic gene biomarkers for predicting survival in patients with acute myeloid leukemia","volume":"10","author":"Huang","year":"2017","journal-title":"Onco Targets Ther"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: new perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu684","article-title":"DOSE: an R\/Bioconductor package for disease ontology semantic and enrichment analysis","volume":"31","author":"Yu","year":"2015","journal-title":"Bioinformatics"},{"volume-title":"org.Hs.eg.db: Genome wide annotation for Human","year":"2019","author":"Carlson","key":"B20"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt285","article-title":"Pathview: an R\/Bioconductor package for pathway-based data integration and visualization","volume":"29","author":"Luo","year":"2013","journal-title":"Bioinformatics"},{"key":"B23","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-24277-4","volume-title":"ggplot2: Elegant Graphics for Data Analysis","author":"Wickham","year":"2016"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01159","article-title":"Clinical Significance of Serum CA125, CA19-9, CA72-4, and Fibrinogen-to-Lymphocyte Ratio in Gastric Cancer With Peritoneal Dissemination","volume":"9","author":"Huang","year":"2019","journal-title":"Front Oncol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/s41419-019-1362-2","article-title":"ATXN2L upregulated by epidermal growth factor promotes gastric cancer cell invasiveness and oxaliplatin resistance","volume":"10","author":"Lin","year":"2019","journal-title":"Cell Death Dis"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-3673","article-title":"MEIS1 and MEIS2 Expression and Prostate Cancer Progression: A Role For HOXB13 Binding Partners in Metastatic Disease","volume":"24","author":"Bhanvadia","year":"2018","journal-title":"Clin Cancer Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/mc.22840","article-title":"The homeodomain transcription factor MEIS1 triggers chemokine expression and is involved in CD8+ T-lymphocyte infiltration in early stage ovarian cancer","volume":"57","author":"Karapetsas","year":"2018","journal-title":"Mol Carcinog"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3978\/j.issn.2072-1439.2014.06.03","article-title":"Meis1 regulates proliferation of non-small-cell lung cancer cells","volume":"6","author":"Li","year":"2014","journal-title":"J Thorac Dis"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.2174\/1389450118666170724165514","article-title":"Emerging Roles of Meis1 in Cardiac Regeneration, Stem Cells and Cancer","volume":"19","author":"Aksoz","year":"2018","journal-title":"Curr Drug Targets"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s12029-016-9824-6","article-title":"Correlation Between Meis1 and Msi1 in Esophageal Squamous Cell Carcinoma","volume":"47","author":"Moghbeli","year":"2016","journal-title":"J Gastrointest Cancer"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2017.112","article-title":"Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia","volume":"25","author":"Abu-Libdeh","year":"2017","journal-title":"Eur J Hum Genet"},{"key":"B32","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1111\/pin.12235","article-title":"Overexpression of PGC1alpha and accumulation of p62 in apocrine carcinoma of the breast","volume":"65","author":"Fuchinoue","year":"2015","journal-title":"Pathol Int"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12092548","article-title":"Cytochrome C Oxidase Subunit 4 (COX4): A Potential Therapeutic Target for the Treatment of Medullary Thyroid Cancer","volume":"12","author":"Bikas","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2008.01.006","article-title":"IkappaB kinase beta (IKKbeta\/IKK2\/IKBKB)\u2013a key molecule in signaling to the transcription factor NF-kappaB","volume":"19","author":"Schmid","year":"2008","journal-title":"Cytokine Growth Factor Rev"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.1331","article-title":"Signaling via the NFkappaB system","volume":"8","author":"Mitchell","year":"2016","journal-title":"Wiley Interdiscip Rev Syst Biol Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8056","article-title":"MicroRNA-16 sensitizes breast cancer cells to paclitaxel through suppression of IKBKB expression","volume":"7","author":"Tang","year":"2016","journal-title":"Oncotarget"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13543","article-title":"A negative feedback loop between miR-200b and the nuclear factor-kappaB pathway via IKBKB\/IKK-beta in breast cancer cells","volume":"283","author":"Wu","year":"2016","journal-title":"FEBS J"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-17-0157","article-title":"IKKbeta-Mediated Resistance to Skin Cancer Development Is Ink4a\/Arf-Dependent","volume":"15","author":"Page","year":"2017","journal-title":"Mol Cancer Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.06.113","article-title":"Inhibition of microRNA-16 facilitates the paclitaxel resistance by targeting IKBKB via NF-kappaB signaling pathway in hepatocellular carcinoma","volume":"503","author":"Huang","year":"2018","journal-title":"Biochem Biophys Res Commun"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-00918","article-title":"Predictors of Survival in Adrenocortical Carcinoma: An Analysis From the National Cancer Database","volume":"103","author":"Tella","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12010247","article-title":"Sterol O-Acyl Transferase 1 as a Prognostic Marker of Adrenocortical Carcinoma","volume":"12","author":"Lacombe","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.18.5678","article-title":"Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival","volume":"27","author":"de Reynies","year":"2009","journal-title":"J Clin Oncol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-3298","article-title":"DNA methylation profiling identifies global methylation differences and markers of adrenocortical tumors","volume":"97","author":"Rechache","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.21978","article-title":"Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors","volume":"51","author":"Fonseca","year":"2012","journal-title":"Genes Chromosomes Cancer"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-2993","article-title":"Identification of a CpG island methylator phenotype in adrenocortical carcinomas","volume":"98","author":"Barreau","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B46","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.canlet.2017.02.016","article-title":"Prognostic alternative mRNA splicing signature in non-small cell lung cancer","volume":"393","author":"Li","year":"2017","journal-title":"Cancer Lett"},{"key":"B47","doi-asserted-by":"publisher","first-page":"796","DOI":"10.21037\/atm.2019.08.63","article-title":"In-depth mining of clinical data: the construction of clinical prediction model with R","volume":"7","author":"Zhou","year":"2019","journal-title":"Ann Transl Med"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.538364\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T07:03:13Z","timestamp":1615532593000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.538364\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,12]]},"references-count":47,"alternative-id":["10.3389\/fendo.2021.538364"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.538364","relation":{},"ISSN":["1664-2392"],"issn-type":[{"type":"electronic","value":"1664-2392"}],"subject":[],"published":{"date-parts":[[2021,3,12]]},"article-number":"538364"}}