Warsow, Gregor, Huebschmann, Daniel ORCID: 0000-0002-6041-7049, Kleinheinz, Kortine ORCID: 0000-0002-1859-2281, Nientiedt, Cathleen, Heller, Martina, Van Coile, Laura, Tolstov, Yanis, Trennheuser, Lukas, Wieczorek, Kathrin, Pecqueux, Carine, Gasch, Claudia, Kuru, Timur, Nyarangi-Dix, Joanne, Hatiboglu, Gencay, Teber, Dogu, Perner, Sven, Stenzinger, Albrecht, Roth, Wilfried, Hadaschik, Boris ORCID: 0000-0002-1052-2692, Pahernik, Sascha, Jaeger, Dirk, Gruellich, Carsten, Duensing, Anette ORCID: 0000-0002-0168-4067, Eils, Roland ORCID: 0000-0002-0034-4036, Schlesner, Matthias ORCID: 0000-0002-5896-4086, Sueltmann, Holger, Hohenfellner, Markus and Duensing, Stefan (2018). Genomic features of renal cell carcinoma with venous tumor thrombus. Sci Rep, 8. LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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Abstract

A venous tumor thrombus (VTT) is a potentially lethal complication of renal cell carcinoma (RCC) but virtually nothing is known about the underlying natural history. Based on our observation that venous thrombi contain significant numbers of viable tumor cells, we applied multiregion whole exome sequencing to a total of 37 primary tumor and VTT samples including normal tissue specimens from five consecutive patients. Our findings demonstrate mutational heterogeneity between primary tumor and VTT with 106 of 483 genes (22%) harboring functional SNVs and/or indels altered in either primary tumor or thrombus. Reconstruction of the clonal phylogeny showed clustering of tumor samples and VTT samples, respectively, in the majority of tumors. However, no new subclones were detected suggesting that pre-existing subclones of the primary tumor drive VTT formation. Importantly, we found several lines of evidence for BRCAness in a subset of tumors. These included mutations in genes that confer BRCAness, a mutational signature and an increase of small indels. Re-analysis of SNV calls from the TCGA KIRC-US cohort confirmed a high frequency of the BRCAness mutational signature AC3 in clear cell RCC. Our findings warrant further pre-clinical experiments and may lead to novel personalized therapies for RCC patients.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Warsow, GregorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huebschmann, DanielUNSPECIFIEDorcid.org/0000-0002-6041-7049UNSPECIFIED
Kleinheinz, KortineUNSPECIFIEDorcid.org/0000-0002-1859-2281UNSPECIFIED
Nientiedt, CathleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heller, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Coile, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tolstov, YanisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trennheuser, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wieczorek, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pecqueux, CarineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gasch, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuru, TimurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nyarangi-Dix, JoanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hatiboglu, GencayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teber, DoguUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stenzinger, AlbrechtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roth, WilfriedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hadaschik, BorisUNSPECIFIEDorcid.org/0000-0002-1052-2692UNSPECIFIED
Pahernik, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jaeger, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gruellich, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duensing, AnetteUNSPECIFIEDorcid.org/0000-0002-0168-4067UNSPECIFIED
Eils, RolandUNSPECIFIEDorcid.org/0000-0002-0034-4036UNSPECIFIED
Schlesner, MatthiasUNSPECIFIEDorcid.org/0000-0002-5896-4086UNSPECIFIED
Sueltmann, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hohenfellner, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duensing, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-186525
DOI: 10.1038/s41598-018-25544-z
Journal or Publication Title: Sci Rep
Volume: 8
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2045-2322
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HOMOLOGY-DIRECTED REPAIR; VENA-CAVA; INTRATUMOR HETEROGENEITY; MUTATIONAL PROCESSES; SIGNATURES; CANCER; BRCA2; HETEROZYGOSITY; RECOMBINATION; CONSISTENCYMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18652

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