{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T05:55:50Z","timestamp":1788587750464,"version":"build-2803163510"},"reference-count":119,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014732","name":"Neurofibromatosis Therapy Acceleration Program","doi-asserted-by":"publisher","award":["3070-37791"],"award-info":[{"award-number":["3070-37791"]}],"id":[{"id":"10.13039\/100014732","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Sarcomas are highly aggressive cancers that have a high propensity for metastasis, fail to respond to conventional therapies, and carry a poor 5-year survival rate. This is particularly true for patients with neurofibromatosis type 1 (NF1), in which 8%\u201313% of affected individuals will develop a malignant peripheral nerve sheath tumor (MPNST). Despite continued research, no effective therapies have emerged from recent clinical trials based on preclinical work. One explanation for these failures could be the lack of attention to intra-tumoral heterogeneity. Prior studies have relied on a single sample from these tumors, which may not be representative of all subclones present within the tumor. In the current study, samples were taken from three distinct areas within a single tumor from a patient with an NF1-MPNST. Whole exome sequencing, RNA sequencing, and copy number analysis were performed on each sample. A blood sample was obtained as a germline DNA control. Distinct mutational signatures were identified in different areas of the tumor as well as significant differences in gene expression among the spatially distinct areas, leading to an understanding of the clonal evolution within this patient. These data suggest that multi-regional sampling may be important for driver gene identification and biomarker development in the future.<\/jats:p>","DOI":"10.3390\/genes11050499","type":"journal-article","created":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T06:41:20Z","timestamp":1588660880000},"page":"499","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Unmasking Intra-Tumoral Heterogeneity and Clonal Evolution in NF1-MPNST"],"prefix":"10.3390","volume":"11","author":[{"given":"Chang-In","family":"Moon","sequence":"first","affiliation":[{"name":"Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Tompkins","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxi","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Godec","sequence":"additional","affiliation":[{"name":"College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4118-7743","authenticated-orcid":false,"given":"Patrik","family":"Pipkorn","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Division of Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Siteman Cancer Center, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Siteman Cancer Center, St. Louis, MO 63110, USA"},{"name":"McDonnell Genome Institute, Division of Oncology\u2014Stem Cell Biology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Dehner","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonika","family":"Dahiya","sequence":"additional","affiliation":[{"name":"Siteman Cancer Center, St. Louis, MO 63110, USA"},{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1719-0771","authenticated-orcid":false,"given":"Angela C.","family":"Hirbe","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Siteman Cancer Center, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.1002\/cncr.20570","article-title":"Validation of the Postoperative Nomogram for 12-Year Sarcoma-Specific Mortality","volume":"101","author":"Eilber","year":"2004","journal-title":"Cancer"},{"key":"ref_2","first-page":"2597","article-title":"Incidence and Survival in Sarcoma in the United States: A Focus on Musculoskeletal Lesions","volume":"33","author":"Ng","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1136\/jmg.39.5.311","article-title":"Malignant peripheral nerve sheath tumours in neurofibromatosis 1","volume":"39","author":"Evans","year":"2002","journal-title":"J. Med. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1002\/1097-0142(19860515)57:10<2006::AID-CNCR2820571022>3.0.CO;2-6","article-title":"Malignant Peripheral Nerve Sheath Tumors. A Clinicopathologic Study of 120 Cases","volume":"57","author":"Ducatman","year":"1986","journal-title":"Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2009\/756395","article-title":"Survival in malignant peripheral nerve sheath tumours: A comparison between sporadic and neurofibromatosis type 1-associated tumours","volume":"2009","author":"Porter","year":"2009","journal-title":"Sarcoma"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1097\/SLA.0b013e3181a77e9a","article-title":"Clinical, pathological, and molecular variables predictive of malignant peripheral nerve sheath tumor outcome","volume":"249","author":"Zou","year":"2009","journal-title":"Ann. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1245\/s10434-012-2573-2","article-title":"Oncologic outcomes of sporadic, neurofibromatosis-associated, and radiation-induced malignant peripheral nerve sheath tumors","volume":"20","author":"LaFemina","year":"2013","journal-title":"Ann. Surg. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1634\/theoncologist.2013-0328","article-title":"Malignant Peripheral Nerve Sheath Tumors","volume":"19","author":"Farid","year":"2014","journal-title":"Oncologist"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1002\/cncr.22098","article-title":"Malignant Peripheral Nerve Sheath Tumors: Prognostic Factors and Survival in a Series of Patients Treated at a Single Institution","volume":"107","author":"Anghileri","year":"2006","journal-title":"Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1245\/s10434-011-1978-7","article-title":"Malignant peripheral nerve sheath tumors (MPNST): The Mayo Clinic experience","volume":"19","author":"Stucky","year":"2012","journal-title":"Ann. Surg. Oncol."},{"key":"ref_11","first-page":"1573","article-title":"International Consensus Statement on Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis","volume":"62","author":"Ferner","year":"2002","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/annonc\/mdq338","article-title":"First-Line Chemotherapy for Malignant Peripheral Nerve Sheath Tumor (MPNST) versus Other Histological Soft Tissue Sarcoma Subtypes and as a Prognostic Factor for MPNST: An EORTC Soft Tissue and Bone Sarcoma Group Study","volume":"22","author":"Kroep","year":"2011","journal-title":"Ann. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.soc.2016.05.009","article-title":"Malignant Peripheral Nerve Sheath Tumor","volume":"25","author":"James","year":"2016","journal-title":"Surg. Oncol. Clin. N. Am."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1126\/science.286.5447.2172","article-title":"Mouse Models of Tumor Development in Neurofibromatosis Type 1","volume":"286","author":"Cichowski","year":"1999","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1126\/science.286.5447.2176","article-title":"Mouse Tumor Model for Neurofibromatosis Type 1","volume":"286","author":"Vogel","year":"1999","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bradtmoller, M., Hartmann, C., Zietsch, J., J\u00e4schke, S., Mautner, V.F., Kurtz, A., Park, S.J., Baier, M., Harder, A., and Reuss, D. (2012). Impaired Pten Expression in Human Malignant Peripheral Nerve Sheath Tumours. PLoS ONE.","DOI":"10.1371\/journal.pone.0047595"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3405","DOI":"10.1158\/0008-5472.CAN-11-4092","article-title":"PTEN and NF1 inactivation in Schwann cells produces a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumors","volume":"72","author":"Keng","year":"2012","journal-title":"Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"19479","DOI":"10.1073\/pnas.0910398106","article-title":"PTEN dosage is essential for neurofibroma development and malignant transformation","volume":"106","author":"Gregorian","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1016\/S0002-9440(10)65504-6","article-title":"Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas","volume":"155","author":"Kourea","year":"1999","journal-title":"Am. J. Path."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"23018","DOI":"10.18632\/oncotarget.25195","article-title":"Aberrant ATRX protein expression is associated with poor overall survival in NF1-MPNST","volume":"9","author":"Lu","year":"2018","journal-title":"Oncotarget"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1038\/ng.3095","article-title":"PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors","volume":"46","author":"Lee","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1093\/carcin\/bgi273","article-title":"Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity","volume":"27","author":"Holtkamp","year":"2006","journal-title":"Carcinogenesis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1172\/JCI7610","article-title":"Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models","volume":"105","author":"DeClue","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7563","DOI":"10.1158\/1078-0432.CCR-11-1707","article-title":"Genomic and molecular characterization of malignant peripheral nerve sheath tumor identifies the IGF1R pathway as a primary target for treatment","volume":"17","author":"Yang","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_25","unstructured":"(1987). Symposium on Linkage of von Recklinghausen Neurofibromatosis (NF1). Closing in on the gene for von Recklinghausen neurofibromatosis. Genomics, 1, 335\u2013383."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Talevich, E., Shain, A.H., Botton, T., and Bastian, B.C. (2016). CNVkit: Genome-Wide Copy Number Detection and Visualization from Targeted DNA Sequencing. PLoS Comput. Biol., 12.","DOI":"10.1371\/journal.pcbi.1004873"},{"key":"ref_27","unstructured":"Li, H. (2013). Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv Preprint."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1093\/bioinformatics\/btv710","article-title":"Manta: Rapid detection of structural variants and indels for germline and cancer sequencing applications","volume":"32","author":"Chen","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1101\/gr.129684.111","article-title":"VarScan 2: Somatic mutation and copy number alteration discovery in cancer by exome sequencing","volume":"22","author":"Koboldt","year":"2012","journal-title":"Genome Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/s41592-018-0051-x","article-title":"Strelka2: Fast and accurate calling of germline and somatic variants","volume":"15","author":"Kim","year":"2018","journal-title":"Nat. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nbt.2514","article-title":"Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples","volume":"31","author":"Cibulskis","year":"2013","journal-title":"Nat. Biotechnol."},{"key":"ref_32","first-page":"2865","article-title":"Pindel: A pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads","volume":"25","author":"Ye","year":"2009","journal-title":"Bioinformatics (Oxford, England)"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"McLaren, W., Gil, L., Hunt, S.E., Riat, H.S., Ritchie, G.R., Thormann, A., Flicek, P., and Cunningham, F. (2016). The Ensembl Variant Effect Predictor. Genome Biol., 17.","DOI":"10.1186\/s13059-016-0974-4"},{"key":"ref_34","unstructured":"(2020, February 24). Bioconductor: Genomic Visualizations in R. Available online: https:\/\/bioconductor.org\/packages\/release\/bioc\/html\/GenVisR.html."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/sj.bjc.6601894","article-title":"The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website","volume":"91","author":"Bamford","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1093\/nar\/gkv1222","article-title":"ClinVar: Public archive of interpretations of clinically relevant variants","volume":"44","author":"Landrum","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"Pauline","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat Methods"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Miller, C.A., White, B.S., Dees, N.D., Griffith, M., Welch, J.S., Griffith, O.L., Vij, R., Tomasson, M.H., Graubert, T.A., and Walter, M.J. (2014). SciClone: Inferring clonal architecture and tracking the spatial and temporal patterns of tumor evolution. PLoS Comput. Biol.","DOI":"10.1371\/journal.pcbi.1003665"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3076","DOI":"10.1093\/annonc\/mdx517","article-title":"ClonEvol: Clonal ordering and visualization in cancer sequencing","volume":"28","author":"Dang","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3150","DOI":"10.1093\/nar\/gkl396","article-title":"An expectation-maximization algorithm for probabilistic reconstructions of full-length isoforms from splice graphs","volume":"34","author":"Xing","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_43","unstructured":"Warnes, G.R., Bolker, B., Bonebakker, L., Gentleman, R., Huber, W., Liaw, A., Lumley, T., Maechler, M., Magnusson, A., and Moeller, S. (2020, April 29). gplots: Various R Programming Tools for Plotting Data. Available online: https:\/\/www.scienceopen.com\/document?vid=0e5d8e31-1fe4-492f-a3d8-8cd71b2b8ad9."},{"key":"ref_44","unstructured":"(2020, February 24). Partek Flow Documentation: Gene-specific Analysis. Available online: https:\/\/documentation.partek.com\/display\/FLOWDOC\/Gene-specific+Analysis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1101\/gr.772403","article-title":"PANTHER: A library of protein families and subfamilies indexed by function","volume":"13","author":"Thomas","year":"2003","journal-title":"Genome Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1200\/JCO.1997.15.1.350","article-title":"Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma","volume":"15","author":"Guillou","year":"1997","journal-title":"J. Clin. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Gao, J., Aksoy, B.A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S.O., Sun, Y., Jacobsen, A., Sinha, R., and Larsson, E. (2013). Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal.","DOI":"10.1126\/scisignal.2004088"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Wang, T., Wang, H., Yang, S., Guo, H., Zhang, B., Guo, H., Wang, L., Zhu, G., Zhang, Y., and Zhou, H. (2018). Association of APEX1 and OGG1 gene polymorphisms with breast cancer risk among Han women in the Gansu Province of China. BMC Med. Genet., 19.","DOI":"10.1186\/s12881-018-0578-9"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6097","DOI":"10.21873\/anticanres.13817","article-title":"Evaluation and Clinical Significance of Jagged-1-activated Notch Signaling by APEX1 in Colorectal Cancer","volume":"39","author":"Kim","year":"2019","journal-title":"Anticancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15","DOI":"10.4174\/astr.2017.92.1.15","article-title":"Clinical implications of APEX1 and Jagged1 as chemoresistance factors in biliary tract cancer","volume":"92","author":"Kim","year":"2017","journal-title":"Ann. Surg. Treat. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.molcel.2018.09.033","article-title":"Exon Junction Complex Shapes the Transcriptome by Repressing Recursive Splicing","volume":"72","author":"Blazquez","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.biopha.2018.05.111","article-title":"MicroRNA-196b enhances the radiosensitivity of SNU-638 gastric cancer cells by targeting RAD23B","volume":"105","author":"Shen","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3212","DOI":"10.1021\/pr4012156","article-title":"Identification and functional validation of RAD23B as a potential protein in human breast cancer progression","volume":"13","author":"Linge","year":"2014","journal-title":"J. Proteome Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1158\/0008-5472.CAN-16-1919","article-title":"SRSF2 Regulates Alternative Splicing to Drive Hepatocellular Carcinoma Development","volume":"77","author":"Luo","year":"2017","journal-title":"Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2659","DOI":"10.1038\/s41375-018-0152-7","article-title":"SRSF2 mutations drive oncogenesis by activating a global program of aberrant alternative splicing in hematopoietic cells","volume":"32","author":"Liang","year":"2018","journal-title":"Leukemia"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1159\/000492649","article-title":"Long Noncoding RNA BCYRN1 Promotes the Proliferation of Colorectal Cancer Cells via Up-Regulating NPR3 Expression","volume":"48","author":"Gu","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.3892\/or.2017.5543","article-title":"P21 activated kinase 4 binds translation elongation factor eEF1A1 to promote gastric cancer cell migration and invasion","volume":"37","author":"Li","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.tice.2018.05.014","article-title":"Eukaryotic elongation factors 2 promotes tumor cell proliferation and correlates with poor prognosis in ovarian cancer","volume":"53","author":"Shi","year":"2018","journal-title":"Tissue Cell"},{"key":"ref_59","first-page":"2343","article-title":"PSMB4 overexpression enhances the cell growth and viability of breast cancer cells leading to a poor prognosis","volume":"40","author":"Wang","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1007\/s00404-015-3904-x","article-title":"PSMB4 expression associates with epithelial ovarian cancer growth and poor prognosis","volume":"293","author":"Liu","year":"2016","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1007\/s11427-016-0018-0","article-title":"The role of ribosomal proteins in the regulation of cell proliferation, tumorigenesis, and genomic integrity","volume":"59","author":"Xu","year":"2016","journal-title":"Sci. China Life Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1089\/jir.2012.0106","article-title":"Regulation of snoRNAs in Cancer: Close Encounters with Interferon","volume":"33","author":"Nallar","year":"2013","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Falaleeva, M., Welden, J.R., Duncan, M.J., and Stamm, S. (2017). C\/D-box snoRNAs form methylating and non-methylating ribonucleoprotein complexes: Old dogs show new tricks. Bioessays, 39.","DOI":"10.1002\/bies.201600264"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1002\/jcb.26301","article-title":"Actin \u03b3 1, a new skin cancer pathogenic gene, identified by the biological feature-based classification","volume":"119","author":"Dong","year":"2018","journal-title":"J. Cell Biochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"387","DOI":"10.3892\/mmr.2013.1831","article-title":"Loss of ASAP3 destabilizes cytoskeletal protein ACTG1 to suppress cancer cell migration","volume":"9","author":"Luo","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/s41586-018-0453-z","article-title":"The NORAD lncRNA assembles a topoisomerase complex critical for genome stability","volume":"561","author":"Munschauer","year":"2018","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"659","DOI":"10.3892\/ijo.2014.2451","article-title":"Loss of ARHGDIA expression is associated with poor prognosis in HCC and promotes invasion and metastasis of HCC cells","volume":"45","author":"Liang","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1111\/bjd.18095","article-title":"Tumour-cell-derived complement components C1r and C1s promote growth of cutaneous squamous cell carcinoma","volume":"182","author":"Viiklepp","year":"2020","journal-title":"Br. J. Dermatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41389-018-0103-1","article-title":"CBX2 identified as driver of anoikis escape and dissemination in high grade serous ovarian cancer","volume":"7","author":"Wheeler","year":"2018","journal-title":"Oncogenesis"},{"key":"ref_70","first-page":"211","article-title":"Collagen 1A1 (COL1A1) promotes metastasis of breast cancer and is a potential therapeutic target","volume":"25","author":"Liu","year":"2018","journal-title":"Discov. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/nrc2222","article-title":"Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis","volume":"7","author":"Menendez","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1038\/s41416-019-0413-x","article-title":"High filamin-C expression predicts enhanced invasiveness and poor outcome in glioblastoma multiforme","volume":"120","author":"Kamil","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.bbagen.2007.09.017","article-title":"Kank proteins: A new family of ankyrin-repeat domain-containing proteins","volume":"1780","author":"Zhu","year":"2008","journal-title":"Biochim. Biophys. Act"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.bcp.2018.01.035","article-title":"Melanoma antigen-D2 controls cell cycle progression and modulates the DNA damage response","volume":"153","author":"Trussart","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.2217\/fon-2017-0672","article-title":"Downregulation of MAGE family member H1 enhances hepatocellular carcinoma progression and serves as a biomarker for patient prognosis","volume":"14","author":"Wang","year":"2018","journal-title":"Future Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e2603","DOI":"10.1038\/cddis.2016.352","article-title":"MCM7 promotes cancer progression through cyclin D1-dependent signaling and serves as a prognostic marker for patients with hepatocellular carcinoma","volume":"8","author":"Qu","year":"2017","journal-title":"Cell Death Dis"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.ccell.2017.10.001","article-title":"Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis","volume":"32","author":"Nguyen","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1111\/cas.13563","article-title":"Stomatin-like protein 2 inhibits cisplatin-induced apoptosis through MEK\/ERK signaling and the mitochondrial apoptosis pathway in cervical cancer cells","volume":"109","author":"Hu","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"6050","DOI":"10.3892\/mmr.2017.7361","article-title":"Effect of silencing the T-Box transcription factor TBX2 in prostate cancer PC3 and LNCaP cells","volume":"16","author":"Du","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_80","first-page":"63","article-title":"The complexity of TRIM28 contribution to cancer","volume":"29","author":"Mazurek","year":"2017","journal-title":"J. Biomed. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"608","DOI":"10.2174\/1566524018666180308111238","article-title":"VCP\/p97\/Cdc48, A Linking of Protein Homeostasis and Cancer Therapy","volume":"17","author":"Lan","year":"2017","journal-title":"Curr. Mol. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3013","DOI":"10.1158\/0008-5472.CAN-16-3168","article-title":"Expression of Neuroendocrine Factor VGF in Lung Cancer Cells Confers Resistance to EGFR Kinase Inhibitors and Triggers Epithelial-to-Mesenchymal Transition","volume":"77","author":"Hwang","year":"2017","journal-title":"Cancer Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"8482","DOI":"10.1002\/jcp.26786","article-title":"Mcl-1 targeting could be an intriguing perspective to cure cancer","volume":"233","author":"Vento","year":"2018","journal-title":"J. Cell Physiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.chembiol.2016.03.017","article-title":"GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity","volume":"23","author":"Louie","year":"2016","journal-title":"Cell Chem. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"18556","DOI":"10.1038\/s41598-019-54973-7","article-title":"A negative feedback mechanism links UBC gene expression to ubiquitin levels by affecting RNA splicing rather than transcription","volume":"9","author":"Bianchi","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","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":"ref_87","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1530\/ERC-13-0231","article-title":"IGF2 and cancer","volume":"20","author":"Livingstone","year":"2013","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1159\/000492978","article-title":"The Dysregulated Expression of KCNQ1OT1 and Its Interaction with Downstream Factors miR-145\/CCNE2 in Breast Cancer Cells","volume":"49","author":"Feng","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"34177","DOI":"10.18632\/oncotarget.10918","article-title":"CRISPR Cas9-guided chromatin immunoprecipitation identifies miR483 as an epigenetic modulator of IGF2 imprinting in tumors","volume":"8","author":"Zhang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.cca.2019.12.023","article-title":"Role of SNHG16 in human cancer","volume":"503","author":"Gong","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/ng.2891","article-title":"Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing","volume":"46","author":"Gerlinger","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/nm.3886","article-title":"Subclonal diversification of primary breast cancer revealed by multiregion sequencing","volume":"21","author":"Yates","year":"2015","journal-title":"Nat. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1038\/ng.3683","article-title":"Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma","volume":"48","author":"Hao","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1056\/NEJMoa1616288","article-title":"Tracking the evolution of non-small-cell lung cancer","volume":"376","author":"Wilson","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4765","DOI":"10.1158\/0008-5472.CAN-15-3476","article-title":"Multiregion whole-exome sequencing uncovers the genetic evolution and mutational heterogeneity of early-stage metastatic melanoma","volume":"76","author":"Harbst","year":"2016","journal-title":"Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3672","DOI":"10.1158\/0008-5472.CAN-17-3167","article-title":"Genomic Status of MET Potentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors","volume":"78","author":"Peacock","year":"2018","journal-title":"Cancer Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1002\/humu.23552","article-title":"Analysis of intratumor heterogeneity in Neurofibromatosis type 1 plexiform neurofibromas and neurofibromas with atypical features: Correlating histological and genomic findings","volume":"39","author":"Gel","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1126\/science.1131262","article-title":"Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure","volume":"314","author":"Nackley","year":"2006","journal-title":"Science"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1126\/science.1135308","article-title":"A \u201csilent\u201d polymorphism in the MDR1 gene changes substrate specificity","volume":"315","author":"Oh","year":"2007","journal-title":"Science"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1126\/science.1170160","article-title":"Coding-sequence determinants of gene expression in Escherichia coli","volume":"324","author":"Kudla","year":"2009","journal-title":"Science"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/nrg3051","article-title":"Understanding the contribution of synonymous mutations to human disease","volume":"12","author":"Sauna","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"14358","DOI":"10.1038\/s41598-017-14067-8","article-title":"In-silico gene essentiality analysis of polyamine biosynthesis reveals APRT as a potential target in cancer","volume":"7","author":"Pey","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.yexcr.2018.06.014","article-title":"PAG1 promotes the inherent radioresistance of laryngeal cancer cells via activation of STAT3","volume":"370","author":"Shen","year":"2018","journal-title":"Exp. Cell Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"24018","DOI":"10.18632\/oncotarget.8116","article-title":"Transmembrane adaptor protein PAG1 is a novel tumor suppressor in neuroblastoma","volume":"7","author":"Agarwal","year":"2016","journal-title":"Oncotarget"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.prp.2014.11.013","article-title":"High expression of vacuolar protein sorting 4B (VPS4B) is associated with accelerated cell proliferation and poor prognosis in human hepatocellular carcinoma","volume":"211","author":"Jiang","year":"2015","journal-title":"Pathol. Res. Pract."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s11010-013-1699-2","article-title":"Vacuolar protein sorting 4B, an ATPase protein positively regulates the progression of NSCLC via promoting cell division","volume":"381","author":"Liu","year":"2013","journal-title":"Mol. Cell Biochem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1128\/MCB.06053-11","article-title":"Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia","volume":"32","author":"Lin","year":"2012","journal-title":"Mol. Cell Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1038\/onc.2016.377","article-title":"ZNF750 is a lineage-specific tumour suppressor in squamous cell carcinoma","volume":"36","author":"Hazawa","year":"2017","journal-title":"Oncogene"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1038\/s41419-018-1224-3","article-title":"m6A-mediated ZNF750 repression facilitates nasopharyngeal carcinoma progression","volume":"5","author":"Zhang","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3892\/mco.2016.961","article-title":"Prognostic significance of Tspan9 in gastric cancer","volume":"5","author":"Feng","year":"2016","journal-title":"Mol. Clin. Oncol."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Qi, Y., Lv, J., Liu, S., Sun, L., Wang, Y., Li, H., Qi, W., and Qiu, W. (2019). TSPAN9 and EMILIN1 synergistically inhibit the migration and invasion of gastric cancer cells by increasing TSPAN9 expression. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5810-2"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"7869","DOI":"10.1073\/pnas.1722617115","article-title":"Estrogen-regulated feedback loop limits the efficacy of estrogen receptor\u2013targeted breast cancer therapy","volume":"115","author":"Xiao","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Smith, H.W., Hirukawa, A., Sanguin-Gendreau, V., Nandi, I., Dufour, C.R., Zuo, D., Tandoc, K., Leibovitch, M., Singh, S., and Rennhack, J.P. (2019). An ErbB2\/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis. Nat. Commun., 10.","DOI":"10.1038\/s41467-019-10681-4"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"22060","DOI":"10.18632\/oncotarget.4279","article-title":"Downregulation of c-SRC kinase CSK promotes castration resistant prostate cancer and pinpoints a novel disease subclass","volume":"6","author":"Yang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"4026","DOI":"10.4049\/jimmunol.172.7.4026","article-title":"Intralesional injection of adenovirus encoding CC chemokine ligand 16 inhibits mammary tumor growth and prevents metastatic-induced death after surgical removal of the treated primary tumor","volume":"172","author":"Guiducci","year":"2004","journal-title":"J. Immunol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1159\/000346797","article-title":"Genomic heterogeneity in acute leukemia","volume":"139","author":"Paulsson","year":"2013","journal-title":"Cytogenet. Genome Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1186\/s13059-014-0525-9","article-title":"Characterizing heterogeneity in leukemic cells using single-cell gene expression analysis","volume":"15","author":"Saadatpour","year":"2014","journal-title":"Genome Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/nature09807","article-title":"Tumor evolution inferred by single cell sequencing","volume":"472","author":"Navin","year":"2011","journal-title":"Nature"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.cell.2012.02.025","article-title":"Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor","volume":"148","author":"Xu","year":"2012","journal-title":"Cell"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/5\/499\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:09:46Z","timestamp":1760364586000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/5\/499"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,1]]},"references-count":119,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["genes11050499"],"URL":"https:\/\/doi.org\/10.3390\/genes11050499","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,1]]}}}