Lorenz, Susanne, Baroy, Tale, Sun, Jinchang, Nome, Torfinn ORCID: 0000-0003-1659-132X, Vodak, Daniel ORCID: 0000-0003-0015-6577, Bryne, Jan-Christian, Hakelien, Anne-Mari, Fernandez-Cuesta, Lynnette ORCID: 0000-0002-0724-6703, Moehlendick, Birte, Rieder, Harald, Szuhai, Karoly ORCID: 0000-0002-1228-4245, Zaikova, Olga, Ahlquist, Terje C., Thomassen, Gard O. S., Skotheim, Rolf I. ORCID: 0000-0002-5609-4048, Lothe, Ragnhild A., Tarpey, Patrick S., Campbell, Peter, Flanagan, Adrienne, Myklebost, Ola and Meza-Zepeda, Leonardo A. (2016). Unscrambling the genomic chaos of osteosarcoma reveals extensive transcript fusion, recurrent rearrangements and frequent novel TP53 aberrations. Oncotarget, 7 (5). S. 5273 - 5289. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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Abstract

In contrast to many other sarcoma subtypes, the chaotic karyotypes of osteosarcoma have precluded the identification of pathognomonic translocations. We here report hundreds of genomic rearrangements in osteosarcoma cell lines, showing clear characteristics of microhomology-mediated break-induced replication (MMBIR) and end-joining repair (MMEJ) mechanisms. However, at RNA level, the majority of the fused transcripts did not correspond to genomic rearrangements, suggesting the involvement of trans-splicing, which was further supported by typical trans-splicing characteristics. By combining genomic and transcriptomic analysis, certain recurrent rearrangements were identified and further validated in patient biopsies, including a PMP22-ELOVL5 gene fusion, genomic structural variations affecting RB1, MTAP/CDKN2A and MDM2, and, most frequently, rearrangements involving TP53. Most cell lines (7/11) and a large fraction of tumor samples (10/25) showed TP53 rearrangements, in addition to somatic point mutations (6 patient samples, 1 cell line) and MDM2 amplifications (2 patient samples, 2 cell lines). The resulting inactivation of p53 was demonstrated by a deficiency of the radiation-induced DNA damage response. Thus, TP53 rearrangements are the major mechanism of p53 inactivation in osteosarcoma. Together with active MMBIR and MMEJ, this inactivation probably contributes to the exceptional chromosomal instability in these tumors. Although rampant rearrangements appear to be a phenotype of osteosarcomas, we demonstrate that among the huge number of probable passenger rearrangements, specific recurrent, possibly oncogenic, events are present. For the first time the genomic chaos of osteosarcoma is characterized so thoroughly and delivered new insights in mechanisms involved in osteosarcoma development and may contribute to new diagnostic and therapeutic strategies.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lorenz, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baroy, TaleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sun, JinchangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nome, TorfinnUNSPECIFIEDorcid.org/0000-0003-1659-132XUNSPECIFIED
Vodak, DanielUNSPECIFIEDorcid.org/0000-0003-0015-6577UNSPECIFIED
Bryne, Jan-ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hakelien, Anne-MariUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez-Cuesta, LynnetteUNSPECIFIEDorcid.org/0000-0002-0724-6703UNSPECIFIED
Moehlendick, BirteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rieder, HaraldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szuhai, KarolyUNSPECIFIEDorcid.org/0000-0002-1228-4245UNSPECIFIED
Zaikova, OlgaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahlquist, Terje C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomassen, Gard O. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Skotheim, Rolf I.UNSPECIFIEDorcid.org/0000-0002-5609-4048UNSPECIFIED
Lothe, Ragnhild A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tarpey, Patrick S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flanagan, AdrienneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Myklebost, OlaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meza-Zepeda, Leonardo A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-284793
DOI: 10.18632/oncotarget.6567
Journal or Publication Title: Oncotarget
Volume: 7
Number: 5
Page Range: S. 5273 - 5289
Date: 2016
Publisher: IMPACT JOURNALS LLC
Place of Publication: ORCHARD PARK
ISSN: 1949-2553
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENE-EXPRESSION DATA; HUMAN SARCOMAS; BREAST-CANCER; COLORECTAL-CANCER; PROSTATE-CANCER; P53 MUTATIONS; CELL-LINES; MDM2; PROTEIN; COMMONMultiple languages
Oncology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28479

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