{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T04:29:24Z","timestamp":1778732964632,"version":"3.51.4"},"reference-count":38,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T00:00:00Z","timestamp":1660608000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Emerson Collective Count-Me-In challenge"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Angiosarcoma is a rare, devastating malignancy with few curative options for disseminated disease. We analyzed a recently published genomic data set of 48 angiosarcomas and noticed recurrent amplifications of HOXA-cluster genes in 33% of patients. HOXA genes are master regulators of embryonic vascular development and adult neovascularization, which provides a molecular rationale to suspect that amplified HOXA genes act as oncogenes in angiosarcoma. HOXA amplifications typically affected multiple pro-angiogenic HOXA genes and co-occurred with amplifications of CD36 and KDR, whereas the overall mutation rate in these tumors was relatively low. HOXA amplifications were found most commonly in angiosarcomas located in the breast and were rare in angiosarcomas arising in sun-exposed areas on the head, neck, face and scalp. Our data suggest that HOXA-amplified angiosarcoma is a distinct molecular subgroup. Efforts to develop therapies targeting oncogenic HOX gene expression in AML and other sarcomas may have relevance for HOXA-amplified angiosarcoma.<\/jats:p>","DOI":"10.3390\/biom12081124","type":"journal-article","created":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T23:44:25Z","timestamp":1660693465000},"page":"1124","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["HOXA Amplification Defines a Genetically Distinct Subset of Angiosarcomas"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2223-0029","authenticated-orcid":false,"given":"Hongbo M.","family":"Xie","sequence":"first","affiliation":[{"name":"Division of Pediatric Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children\u2019s Hospital of Philadelphia, 3501 Civic Center Boulevard, CTRB 3064, Philadelphia, PA 19104, USA"},{"name":"Department of Bioinformatics and Health Informatics (DBHI), Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0691-356X","authenticated-orcid":false,"given":"Kathrin M.","family":"Bernt","sequence":"additional","affiliation":[{"name":"Division of Pediatric Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children\u2019s Hospital of Philadelphia, 3501 Civic Center Boulevard, CTRB 3064, Philadelphia, PA 19104, USA"},{"name":"Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Abramson Cancer Center, Philadelphia, PA 19106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.critrevonc.2019.04.010","article-title":"Targeting angiosarcomas of the soft tissues: A challenging effort in a heterogeneous and rare disease","volume":"138","author":"Weidema","year":"2019","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Weidema, M.E., Flucke, U.E., van der Graaf, W.T.A., Ho, V.K.Y., Hillebrandt-Roeffen, M.H.S., Dutch Nationwide Network and Registry of Histo- and Cytopathology (PALGA)-Group, Versleijen-Jonkers, Y.M.H., Husson, O., and Desar, I.M.E. (2019). Prognostic Factors in a Large Nationwide Cohort of Histologically Confirmed Primary and Secondary Angiosarcomas. Cancers, 11.","DOI":"10.3390\/cancers11111780"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41591-019-0749-z","article-title":"The Angiosarcoma Project: Enabling genomic and clinical discoveries in a rare cancer through patient-partnered research","volume":"26","author":"Painter","year":"2020","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/ng.2921","article-title":"Recurrent PTPRB and PLCG1 mutations in angiosarcoma","volume":"46","author":"Behjati","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"36041","DOI":"10.18632\/oncotarget.5936","article-title":"Targeted massively parallel sequencing of angiosarcomas reveals frequent activation of the mitogen activated protein kinase pathway","volume":"6","author":"Murali","year":"2015","journal-title":"Oncotarget"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5878","DOI":"10.1002\/cncr.27614","article-title":"Alterations of the p53 and PIK3CA\/AKT\/mTOR pathways in angiosarcomas: A pattern distinct from other sarcomas with complex genomics","volume":"118","author":"Italiano","year":"2012","journal-title":"Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3892\/ijo.2015.2989","article-title":"Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts","volume":"47","author":"Andersen","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"24750","DOI":"10.18632\/oncotarget.25345","article-title":"Combined mTOR and MEK inhibition is an effective therapy in a novel mouse model for angiosarcoma","volume":"9","author":"Chadwick","year":"2018","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/labinvest.2014.141","article-title":"Generation of a murine hepatic angiosarcoma cell line and reproducible mouse tumor model","volume":"95","author":"Rothweiler","year":"2015","journal-title":"Lab. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/gcc.20827","article-title":"Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions","volume":"50","author":"Guo","year":"2011","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6173","DOI":"10.1158\/0008-5472.CAN-14-1162","article-title":"A recurrent activating PLCG1 mutation in cardiac angiosarcomas increases apoptosis resistance and invasiveness of endothelial cells","volume":"74","author":"Kunze","year":"2014","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/modpathol.2013.163","article-title":"MYC amplification and overexpression in primary cutaneous angiosarcoma: A fluorescence in-situ hybridization and immunohistochemical study","volume":"27","author":"Shon","year":"2014","journal-title":"Mod. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"457","DOI":"10.4161\/cam.22164","article-title":"The dual roles of homeobox genes in vascularization and wound healing","volume":"6","author":"Kachgal","year":"2012","journal-title":"Cell Adhes. Migr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.bbcan.2017.09.001","article-title":"The role of a new class of long noncoding RNAs transcribed from ultraconserved regions in cancer","volume":"1868","author":"Terracciano","year":"2017","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1126\/science.1098119","article-title":"Ultraconserved elements in the human genome","volume":"304","author":"Bejerano","year":"2004","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1387\/ijdb.180206at","article-title":"HOX genes in normal, engineered and malignant hematopoiesis","volume":"62","author":"Collins","year":"2018","journal-title":"Int. J. Dev. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/350473a0","article-title":"Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5","volume":"350","author":"Chisaka","year":"1991","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"133","DOI":"10.4161\/cam.5.2.14373","article-title":"Temporal changes in Hox gene expression accompany endothelial cell differentiation of embryonic stem cells","volume":"5","author":"Bahrami","year":"2011","journal-title":"Cell Adhes. Migr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/ncb2137","article-title":"HoxA3 is an apical regulator of haemogenic endothelium","volume":"13","author":"Iacovino","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1084\/jem.20042097","article-title":"Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells","volume":"201","author":"Rossig","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5661","DOI":"10.1093\/nar\/20.21.5661","article-title":"Identification of a novel vertebrate homeobox gene expressed in haematopoietic cells","volume":"20","author":"Crompton","year":"1992","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1242\/jcs.02399","article-title":"HOXA3 induces cell migration in endothelial and epithelial cells promoting angiogenesis and wound repair","volume":"118","author":"Mace","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1002\/stem.90","article-title":"HOXA3 modulates injury-induced mobilization and recruitment of bone marrow-derived cells","volume":"27","author":"Mace","year":"2009","journal-title":"Stem Cells"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1182\/blood-2009-12-259549","article-title":"Hoxa3 promotes the differentiation of hematopoietic progenitor cells into proangiogenic Gr-1+CD11b+ myeloid cells","volume":"117","author":"Mahdipour","year":"2011","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1161\/01.RES.0000120861.27064.09","article-title":"Homeobox A9 transcriptionally regulates the EphB4 receptor to modulate endothelial cell migration and tube formation","volume":"94","author":"Bruhl","year":"2004","journal-title":"Circ. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1073\/pnas.93.2.900","article-title":"Restricted expression of homeobox genes distinguishes fetal from adult human smooth muscle cells","volume":"93","author":"Miano","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1089\/lrb.2005.3.240","article-title":"A role for Hox A5 in regulating angiogenesis and vascular patterning","volume":"3","author":"Rhoads","year":"2005","journal-title":"Lymphat. Res. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"185","DOI":"10.4161\/cam.1.4.5448","article-title":"HoxA5 stabilizes adherens junctions via increased Akt1","volume":"1","author":"Arderiu","year":"2007","journal-title":"Cell Adhes. Migr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6721","DOI":"10.1158\/0008-5472.CAN-08-4069","article-title":"Endothelial cell migration and vascular endothelial growth factor expression are the result of loss of breast tissue polarity","volume":"69","author":"Chen","year":"2009","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1158\/2159-8290.CD-16-0237","article-title":"Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia","volume":"6","author":"Kuhn","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ccr.2011.06.010","article-title":"MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L","volume":"20","author":"Bernt","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ccr.2011.06.009","article-title":"Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor","volume":"20","author":"Daigle","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1182\/blood-2017-12-818948","article-title":"The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia","volume":"131","author":"Stein","year":"2018","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"458","DOI":"10.18632\/oncotarget.13444","article-title":"Tumorigenicity of Ewing sarcoma is critically dependent on the trithorax proteins MLL1 and menin","volume":"8","author":"Svoboda","year":"2017","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1158\/1535-7163.MCT-17-0580","article-title":"Pharmacologic Inhibition of the Menin-MLL Interaction Leads to Transcriptional Repression of PEG10 and Blocks Hepatocellular Carcinoma","volume":"17","author":"Kempinska","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_38","unstructured":"(2022, July 04). The Angiosarcoma Project\u2014Count Me In (Nature Medicine, 2020). Available online: https:\/\/www.cbioportal.org\/study\/summary?id=angs_project_painter_2018."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/8\/1124\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:10:44Z","timestamp":1760141444000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/8\/1124"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,16]]},"references-count":38,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["biom12081124"],"URL":"https:\/\/doi.org\/10.3390\/biom12081124","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.05.06.22274708","asserted-by":"object"}]},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,16]]}}}