{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T03:59:51Z","timestamp":1781755191726,"version":"3.54.5"},"reference-count":51,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T00:00:00Z","timestamp":1668729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Interdisciplinary Research Grant from the Higher Colleges of Technology","award":["Interdisciplinary_213346"],"award-info":[{"award-number":["Interdisciplinary_213346"]}]},{"name":"INTI International University","award":["Interdisciplinary_213346"],"award-info":[{"award-number":["Interdisciplinary_213346"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The diagnosis of endometrial cancer involves sequential, invasive tests to assess the thickness of the endometrium by a transvaginal ultrasound scan. In 6\u201333% of cases, endometrial biopsy results in inadequate tissue for a conclusive pathological diagnosis and 6% of postmenopausal women with non-diagnostic specimens are later discovered to have severe endometrial lesions. Thus, identifying diagnostic biomarkers could offer a non-invasive diagnosis for community or home-based triage of symptomatic or asymptomatic women. Herein, this study identified high-risk pathogenic nsSNPs in the NRAS gene. The nsSNPs of NRAS were retrieved from the NCBI database. PROVEAN, SIFT, PolyPhen-2, SNPs&amp;GO, PhD-SNP and PANTHER were used to predict the pathogenicity of the nsSNPs. Eleven nsSNPs were identified as \u201cdamaging\u201d, and further stability analysis using I-Mutant 2.0 and MutPred 2 indicated eight nsSNPs to cause decreased stability (DDG scores &lt; \u22120.5). Post-translational modification and protein\u2013protein interactions (PPI) analysis showed putative phosphorylation sites. The PPI network indicated a GFR-MAPK signalling pathway with higher node degrees that were further evaluated for drug targets. The P34L, G12C and Y64D showed significantly lower binding affinity towards GTP than wild-type. Furthermore, the Kaplan\u2013Meier bioinformatics analyses indicated that the NRAS gene deregulation affected the overall survival rate of patients with endometrial cancer, leading to prognostic significance. Findings from this could be considered novel diagnostic and therapeutic markers.<\/jats:p>","DOI":"10.3390\/ijms232214285","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T03:29:50Z","timestamp":1668742190000},"page":"14285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Identification of NRAS Diagnostic Biomarkers and Drug Targets for Endometrial Cancer\u2014An Integrated in Silico Approach"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0592-5216","authenticated-orcid":false,"given":"Larsen","family":"Alessandro","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Faculty of Applied Sciences, UCSI University, Kuala Lumpur 56000, Malaysia"},{"name":"Advanced Membrane Technology Research Centre (AMTEC), School of Chemical and Energy Engineering (FCEE), Universiti Teknologi Malaysia, Johor 81310, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kat-Jun Eric","family":"Low","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Faculty of Applied Sciences, UCSI University, Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aisha","family":"Abushelaibi","sequence":"additional","affiliation":[{"name":"Health Sciences Division, Abu Dhabi Women\u2019s College, Higher Colleges of Technology, Abu Dhabi P.O. Box 25026, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swee-Hua Erin","family":"Lim","sequence":"additional","affiliation":[{"name":"Health Sciences Division, Abu Dhabi Women\u2019s College, Higher Colleges of Technology, Abu Dhabi P.O. Box 25026, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Hee","family":"Cheng","sequence":"additional","affiliation":[{"name":"Faculty of Health and Life Sciences, INTI International University, Persiaran Perdana BBN, Putra Nilai, Nilai 71800, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1293-8867","authenticated-orcid":false,"given":"Sook-keng","family":"Chang","sequence":"additional","affiliation":[{"name":"Faculty of Health and Life Sciences, INTI International University, Persiaran Perdana BBN, Putra Nilai, Nilai 71800, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kok-Song","family":"Lai","sequence":"additional","affiliation":[{"name":"Health Sciences Division, Abu Dhabi Women\u2019s College, Higher Colleges of Technology, Abu Dhabi P.O. Box 25026, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yap Wai","family":"Sum","sequence":"additional","affiliation":[{"name":"He & Ni Academy, Office Tower B, Northpoint Mid Valley City, Kuala Lumpur 59200, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5617-901X","authenticated-orcid":false,"given":"Sathiya","family":"Maran","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Monash University Malaysia, Subang Jaya 47500, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.ygyno.2021.01.036","article-title":"Variations in incidence and mortality rates of endometrial cancer at the global, regional, and national levels, 1990\u20132019","volume":"161","author":"Gu","year":"2021","journal-title":"Gynecol. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1016\/S0140-6736(22)00323-3","article-title":"Endometrial cancer","volume":"399","author":"Crosbie","year":"2022","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s13669-020-00279-9","article-title":"Tumor Markers in Endometrial Cancer","volume":"9","author":"Aksel","year":"2020","journal-title":"Curr. Obstet. Gynecol. Rep."},{"key":"ref_5","unstructured":"(2022, July 01). OFFICE FOR NATIONAL STATISTICS. CANCER SURVIVAL IN ENGLAND: Adult, Stage at Diagnosis and Childhood-Patients Followed Up\u2026 to 2018. DANDY BOOKSELLERS Limited 2019, Available online: https:\/\/www.ons.gov.uk\/."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/s41573-020-0068-6","article-title":"RAS-targeted therapies: Is the undruggable drugged?","volume":"19","author":"Moore","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/s41568-019-0177-x","article-title":"Clinical Actionability of Molecular Targets in Endometrial Cancer","volume":"19","author":"Urick","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17593","DOI":"10.1002\/jcb.29027","article-title":"Estrogen receptor alpha activates MAPK signaling pathway to promote the development of endometrial cancer","volume":"120","author":"Liu","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S25","DOI":"10.1016\/j.jcyt.2019.03.333","article-title":"Prevalence of ras\/mapk pathway mutation (KRAS, NRAS, and BRAF) in plasma cell myeloma at a single institute in Korea","volume":"21","author":"Han","year":"2019","journal-title":"Cytotherapy"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zhang, H.-H., Wang, H.-S., Qian, X.-W., Fan, C.-Q., Li, J., Miao, H., Zhu, X.-H., Yu, Y., Meng, J.-H., and Cao, P. (2019). Genetic variants and clinical significance of pediatric acute lymphoblastic leukemia. Ann. Transl. Med., 7.","DOI":"10.21037\/atm.2019.04.80"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.ygyno.2015.06.036","article-title":"Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK\/mTOR\/S6 and MAPK signaling","volume":"138","author":"Han","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_12","first-page":"1997","article-title":"ERK\/MAPK signalling pathway and tumorigenesis (Review)","volume":"19","author":"Guo","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s10549-019-05474-8","article-title":"Clinical relevance of H-RAS, K-RAS, and N-RAS mRNA expression in primary breast cancer patients","volume":"179","author":"Fehm","year":"2020","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"102238","DOI":"10.1016\/j.ctrv.2021.102238","article-title":"NRAS mutant melanoma: Towards better therapies","volume":"99","author":"Randic","year":"2021","journal-title":"Cancer Treat. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/bs.apcsb.2018.09.002","article-title":"Protein stability and degradation in health and disease","volume":"114","author":"Clausen","year":"2019","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"baab012","DOI":"10.1093\/database\/baab012","article-title":"Post-translational modifications in proteins: Resources, tools and prediction methods","volume":"2021","author":"Ramazi","year":"2021","journal-title":"Database"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.cell.2019.01.002","article-title":"Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis","volume":"176","author":"Yin","year":"2019","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/nrm3255","article-title":"Regulating the Regulator: Post-Translational Modification of Ras","volume":"13","author":"Ahearn","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1182\/blood.2019003530","article-title":"Genetic disruption of N-RasG12D palmitoylation perturbs hematopoiesis and prevents myeloid transformation in mice","volume":"135","author":"Zambetti","year":"2020","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15262","DOI":"10.1038\/ncomms15262","article-title":"RAF proteins exert both specific and compensatory functions during tumour progression of NRAS-driven melanoma","volume":"8","author":"Dorard","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1002\/ijc.29970","article-title":"MAP kinase pathway gene copy alterations in NRAS\/BRAF wild-type advanced melanoma","volume":"138","author":"Orouji","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1158\/1541-7786.MCR-18-0316","article-title":"Identification and characterization of oncogenic SOS1 mutations in lung adenocarcinoma","volume":"17","author":"Cai","year":"2019","journal-title":"Mol. Cancer Res."},{"key":"ref_23","first-page":"2321","article-title":"Expression of Phosphorylated Akt, mTOR and MAPK in Type I Endometrial Carcinoma: Clinical Significance","volume":"35","author":"Kourea","year":"2015","journal-title":"Anticancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.ygyno.2018.05.028","article-title":"Durable response in a woman with recurrent low-grade endometrioid endometrial cancer and a germline BRCA2 mutation treated with a PARP inhibitor","volume":"150","author":"Gockley","year":"2018","journal-title":"Gynecol. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1093\/carcin\/bgx008","article-title":"Molecular profiles of benign and (pre)malignant endometrial lesions","volume":"38","author":"Tops","year":"2017","journal-title":"Carcinogenesis"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ygyno.2010.11.039","article-title":"Tissue-specific signatures of activating PIK3CA and RAS mutations in carcinosarcomas of gynecologic origin","volume":"121","author":"Growdon","year":"2011","journal-title":"Gynecol. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.gore.2019.01.007","article-title":"Response to trametinib in recurrent low-grade serous ovarian cancer with NRAS mutation: A case report","volume":"28","author":"Champer","year":"2019","journal-title":"Gynecol. Oncol. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Du, X., Li, Y., Xia, Y.L., Ai, S.M., Liang, J., Sang, P., Ji, X.L., and Liu, S.Q. (2016). Insights into Protein\u2013Ligand Interactions: Mechanisms, Models, and Methods. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17020144"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1021\/ct401022c","article-title":"Predicting the impact of missense mutations on protein-protein binding affinity","volume":"10","author":"Li","year":"2014","journal-title":"J. Chem. Theory Comput."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1093\/annonc\/mdv484","article-title":"ESTRO consensus conference on endometrial cancer: Diagnosis, treatment and follow-up","volume":"27","author":"Colombo","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Coll-de la Rubia, E., Martinez-Garcia, E., Dittmar, G., Nazarov, P.V., Bebia, V., Cabrera, S., Gil-Moreno, A., and Col\u00e1s, E. (2021). In silico Approach for Validating and Unveiling New Applications for Prognostic Biomarkers of Endometrial Cancer. Cancers, 13.","DOI":"10.3390\/cancers13205052"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lim, E.C., Lim, S.W., Tan, K.J., Sathiya, M., Cheng, W.H., Lai, K.S., Loh, J.Y., and Yap, W.S. (2022). In-Silico Analysis of Deleterious SNPs of FGF4 Gene and Their Impacts on Protein Structure, Function and Bladder Cancer Prognosis. Life, 12.","DOI":"10.3390\/life12071018"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1093\/bioinformatics\/btv195","article-title":"PROVEAN web server: A tool to predict the functional effect of amino acid substitutions and indels","volume":"31","author":"Choi","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: Predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_35","first-page":"7","article-title":"Predicting functional effect of human missense mutations using PolyPhen-2","volume":"76","author":"Adzhubei","year":"2013","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Bendl, J., Stourac, J., Salanda, O., Pavelka, A., Wieben, E.D., Zendulka, J., Brezovsky, J., and Damborsky, J. (2014). PredictSNP: Robust and accurate consensus classifier for prediction of disease-related mutations. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003440"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Capriotti, E., Calabrese, R., Fariselli, P., Martelli, P.L., Altman, R.B., and Casadio, R. (2013). WS-SNPs&GO: A web server for predicting the deleterious effect of human protein variants using functional annotation. BMC Genom., 14.","DOI":"10.1186\/1471-2164-14-S3-S6"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5918","DOI":"10.1038\/s41467-020-19669-x","article-title":"Inferring the molecular and phenotypic impact of amino acid variants with MutPred2","volume":"11","author":"Pejaver","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"W306","DOI":"10.1093\/nar\/gki375","article-title":"I-Mutant2.0: Predicting stability changes upon mutation from the protein sequence or structure","volume":"33","author":"Capriotti","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1006\/jmbi.1999.3310","article-title":"Sequence and structure-based prediction of eukaryotic protein phosphorylation sites","volume":"294","author":"Blom","year":"1999","journal-title":"J. Mol. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"170167","DOI":"10.1098\/rsob.170167","article-title":"Protein SUMOylation modification and its associations with disease","volume":"7","author":"Yang","year":"2017","journal-title":"Open Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.1002\/elps.201900100","article-title":"MS-based strategies for identification of protein SUMOylation modification","volume":"40","author":"Sheng","year":"2019","journal-title":"Electrophoresis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein\u2013protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein\u2013protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e27633","DOI":"10.2196\/27633","article-title":"Web-based survival analysis tool tailored for medical research (KMplot): Development and implementation","volume":"23","year":"2021","journal-title":"J. Med. Internet Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: Homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminformatics"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14285\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:20:49Z","timestamp":1760145649000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14285"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,18]]},"references-count":51,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232214285"],"URL":"https:\/\/doi.org\/10.3390\/ijms232214285","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,18]]}}}