{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:06:24Z","timestamp":1760148384948,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T00:00:00Z","timestamp":1682467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NSF (Bulgaria) project","award":["KP-06-H41\/2"],"award-info":[{"award-number":["KP-06-H41\/2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: Malignant pleural mesothelioma (MPM) is a rare cancer type with an increasing incidence worldwide. We aimed to develop a rational gene expression-based prognostic score in MPM using publicly available datasets. Methods: We developed and validated a two-gene prognostic score (2-PS) using three independent publicly available gene expression datasets. The 2-PS was built using the Robust Likelihood-Based Survival Modeling with Microarray Data method. Results: We narrowed down the model building to the analysis of 179 genes, which have been shown previously to be of importance to MPM development. Our statistical approach showed that a model including two genes (GOLT1B and MAD2L1) was the best predictor for overall survival (OS) (p &lt; 0.0001). The binary score based on the median of the continuous score stratified the patients into low and high score groups and also showed statistical significance in uni- and multivariate models. The 2-PS was validated using two independent transcriptomic datasets. Furthermore, gene set enrichment analysis using training and validation datasets showed that high score patients had distinct gene expression profiles. Our 2-PS also showed a correlation with the estimated infiltration by some immune cell fractions such as CD8+ T cells and M1\/2 macrophages. Finally, 2-PS correlated with sensitivity or resistance to some commonly used chemotherapeutic drugs. Conclusion: This is the first study to demonstrate good performance of only two-gene expression-based prognostic scores in MPM. Our initial approach for features selection allowed for an increased likelihood for the predictive value of the developed score, which we were also able to demonstrate.<\/jats:p>","DOI":"10.3390\/diagnostics13091556","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T05:23:35Z","timestamp":1682486615000},"page":"1556","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Novel Two-Gene Expression-Based Prognostic Score in Malignant Pleural Mesothelioma"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5362-7999","authenticated-orcid":false,"given":"Velizar","family":"Shivarov","sequence":"first","affiliation":[{"name":"Department of Experimental Research, Medical University Pleven, 5800 Pleven, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5358-5207","authenticated-orcid":false,"given":"Georgi","family":"Blazhev","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Biology, St. Kliment Ohridski Sofia University, 1164 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7719-382X","authenticated-orcid":false,"given":"Angel","family":"Yordanov","sequence":"additional","affiliation":[{"name":"Department of Gynaecological Oncology, Medical University Pleven, 5800 Pleven, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S28","DOI":"10.21037\/tlcr.2019.11.11","article-title":"Epidemiology of mesothelioma in the 21st century in Europe and the United States, 40 years after restricted\/banned asbestos use","volume":"9","author":"Alpert","year":"2020","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e2025109","DOI":"10.1001\/jamanetworkopen.2020.25109","article-title":"Prevalence of high tumor mutational burden and association with survival in patients with less common solid tumors","volume":"3","author":"Shao","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1158\/2159-8290.CD-18-0804","article-title":"Integrative molecular characterization of malignant pleural mesothelioma","volume":"8","author":"Hmeljak","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1016\/S1470-2045(21)00471-X","article-title":"Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): A multicentre, double-blind, randomised, phase 3 trial","volume":"22","author":"Fennell","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.annonc.2022.01.074","article-title":"First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743","volume":"33","author":"Peters","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S2213-2600(20)30515-4","article-title":"Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study","volume":"9","author":"Yap","year":"2021","journal-title":"Lancet Respir. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.thorsurg.2020.08.005","article-title":"The molecular basis of malignant pleural mesothelioma","volume":"30","author":"Wadowski","year":"2020","journal-title":"Thorac. Surg. Clin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/ng.3520","article-title":"Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations","volume":"48","author":"Bueno","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1038\/s41467-019-09307-6","article-title":"Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications","volume":"10","author":"Blum","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/nbt.3460","article-title":"High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines","volume":"34","author":"Yu","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1038\/ng.3984","article-title":"Computational correction of copy number effect improves specificity of CRISPR\u2013Cas9 essentiality screens in cancer cells","volume":"49","author":"Meyers","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.cell.2017.06.010","article-title":"Defining a cancer dependency map","volume":"170","author":"Tsherniak","year":"2017","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/nrg3967","article-title":"An ecosystem of cancer cell line factories to support a cancer dependency map","volume":"16","author":"Boehm","year":"2015","journal-title":"Nat. Rev. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v029.i01","article-title":"Robust likelihood-based survival modeling with microarray data","volume":"29","author":"Cho","year":"2009","journal-title":"J. Stat. Softw."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Budczies, J., Klauschen, F., Sinn, B.V., Gyorffy, B., Schmitt, W.D., Darb-Esfahani, S., and Denkert, C. (2012). Cutoff Finder: A comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0051862"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e454","DOI":"10.3324\/haematol.2016.146555","article-title":"MicroRNA expression-based outcome prediction in acute myeloid leukemia: Novel insights through cross-platform integrative analyses","volume":"101","author":"Shivarov","year":"2016","journal-title":"Haematologica"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.immuni.2018.03.023","article-title":"The immune landscape of cancer","volume":"48","author":"Thorsson","year":"2018","journal-title":"Immunity"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining cell type abundance and expression from bulk tissues with digital cytometry","volume":"37","author":"Newman","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.cell.2016.06.017","article-title":"A landscape of pharmacogenomic interactions in cancer","volume":"166","author":"Iorio","year":"2016","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D955","DOI":"10.1093\/nar\/gks1111","article-title":"Genomics of Drug Sensitivity in Cancer (GDSC): A resource for therapeutic biomarker discovery in cancer cells","volume":"41","author":"Yang","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1097\/JTO.0b013e3181ec173d","article-title":"Receiver operating characteristic curve in diagnostic test assessment","volume":"5","author":"Mandrekar","year":"2010","journal-title":"J. Thorac. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1158\/1078-0432.CCR-0607-3","article-title":"Gene expression profiles predict survival and progression of pleural mesothelioma","volume":"10","author":"Pass","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1158\/1078-0432.CCR-13-2429","article-title":"Molecular classification of malignant pleural mesothelioma: Identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition","volume":"20","author":"Jaurand","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1093\/jnci\/95.8.598","article-title":"Using gene expression ratios to predict outcome among patients with mesothelioma","volume":"95","author":"Gordon","year":"2003","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1016\/S0002-9440(10)62492-3","article-title":"Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling","volume":"166","author":"Gordon","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1093\/jnci\/djp061","article-title":"Four-gene expression ratio test for survival in patients undergoing surgery for mesothelioma","volume":"101","author":"Gordon","year":"2009","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"78","DOI":"10.3389\/fonc.2019.00078","article-title":"Development and validation of a prognostic signature for malignant pleural mesothelioma","volume":"9","author":"Zhou","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"899","DOI":"10.3389\/fgene.2020.00899","article-title":"Identification of a five-gene signature for predicting survival in malignant pleural mesothelioma patients","volume":"11","author":"Bai","year":"2020","journal-title":"Front. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2970","DOI":"10.1158\/0008-5472.CAN-05-3907","article-title":"Global gene expression profiling of pleural mesotheliomas: Overexpression of aurora kinases and P16\/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction","volume":"66","author":"Chuai","year":"2006","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nrm929","article-title":"The spindle checkpoint: Structural insights into dynamic signalling","volume":"3","author":"Musacchio","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Morani, F., Bisceglia, L., Rosini, G., Mutti, L., Melaiu, O., Landi, S., and Gemignani, F. (2021). Identification of overexpressed genes in malignant pleural mesothelioma. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052738"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1093\/annonc\/mdu127","article-title":"Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications","volume":"25","author":"Suraokar","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1158\/1535-7163.MCT-20-0363","article-title":"BRCA1\/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in MesotheliomaBRCA1\/MAD2L1 Expression Predicts Response to Vinorelbine","volume":"20","author":"Busacca","year":"2021","journal-title":"Mol. Cancer Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3934","DOI":"10.1093\/emboj\/18.14.3934","article-title":"Got1p and Sft2p: Membrane proteins involved in traffic to the Golgi complex","volume":"18","author":"Conchon","year":"1999","journal-title":"EMBO J."},{"key":"ref_37","first-page":"6218","article-title":"Genomic and expression analysis of the 12p11-p12 amplicon using EST arrays identifies two novel amplified and overexpressed genes","volume":"62","author":"Bourdon","year":"2002","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1186\/s12935-021-01991-z","article-title":"Vesicle transporter GOLT1B mediates the cell membrane localization of DVL2 and PD-L2 and promotes colorectal cancer metastasis","volume":"21","author":"Liu","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5871","DOI":"10.3389\/fonc.2021.805273","article-title":"Multi-omics analyses revealed GOLT1B as a potential prognostic gene in breast cancer probably regulating the immune microenvironment","volume":"11","author":"Liu","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1038\/s41416-022-01950-z","article-title":"A combination of intrinsic and extrinsic features improves prognostic prediction in malignant pleural mesothelioma","volume":"127","author":"Nguyen","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.lungcan.2022.03.014","article-title":"Prognostic impact of inflammation in malignant pleural mesothelioma: A large-scale analysis of consecutive patients","volume":"166","author":"Fournel","year":"2022","journal-title":"Lung Cancer"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/13\/9\/1556\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:23:28Z","timestamp":1760124208000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/13\/9\/1556"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,26]]},"references-count":41,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["diagnostics13091556"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics13091556","relation":{},"ISSN":["2075-4418"],"issn-type":[{"type":"electronic","value":"2075-4418"}],"subject":[],"published":{"date-parts":[[2023,4,26]]}}}