Styring, E2; Seinen, J2; Dominguez-Valentin, M2; Domanski, H A2; Jönsson, M2; von Steyern, F V2; Hoekstra, H J2; Suurmeijer, A J H2; Nilbert, M3
1 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 unknown3 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
BACKGROUND: Angiosarcomas may develop as primary tumours of unknown cause or as secondary tumours, most commonly following radiotherapy to the involved field. The different causative agents may be linked to alternate tumorigenesis, which led us to investigate the genetic profiles of morphologically indistinguishable primary and secondary angiosarcomas. METHODS: Whole-genome (18k) c-DNA-mediated annealing, selection, extension and ligation analysis was used to genetically profile 26 primary and 29 secondary angiosarcomas. Key findings were thereafter validated using RT-qPCR, immunohistochemistry and validation of the gene signature to an external data set. RESULTS: In total, 103 genes were significantly deregulated between primary and secondary angiosarcomas. Secondary angiosarcomas showed upregulation of MYC, KIT and RET and downregulation of CDKN2C. Functional annotation analysis identified multiple target genes in the receptor protein tyrosine kinase pathway. The results were validated using RT-qPCR and immunohistochemistry. Further, the gene signature was applied to an external data set and, herein, distinguished primary from secondary angiosarcomas. CONCLUSIONS: Upregulation of MYC, KIT and RET and downregulation of CDKN2C characterise secondary angiosarcoma, which implies possibilities for diagnostic application and a mechanistic basis for therapeutic evaluation of RET-kinase-inhibitors in these highly aggressive tumours.
B J C, 2014, Vol 111, Issue 2, p. 407-412
Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Female; Gene Amplification; Genes, myc; Genome, Human; Hemangiosarcoma; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasms, Second Primary; Proto-Oncogene Proteins c-kit; Proto-Oncogene Proteins c-ret; Young Adult; Journal Article; Research Support, Non-U.S. Gov't