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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.
Keywords
HOMOLOGY-DIRECTED REPAIR, DOUBLE-STRAND BREAKS, INTRATUMOR HETEROGENEITY, VENA-CAVA, MUTATIONAL PROCESSES, CANCER, SIGNATURES, VARIANTS, BRCA2, HETEROZYGOSITY

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Chicago
Warsow, Gregor, Daniel Hübschmann, Kortine Kleinheinz, Cathleen Nientiedt, Martina Heller, Laura Van Coile, Yanis Tolstov, et al. 2018. “Genomic Features of Renal Cell Carcinoma with Venous Tumor Thrombus.” Scientific Reports 8.
APA
Warsow, G., Hübschmann, D., Kleinheinz, K., Nientiedt, C., Heller, M., Van Coile, L., Tolstov, Y., et al. (2018). Genomic features of renal cell carcinoma with venous tumor thrombus. SCIENTIFIC REPORTS, 8.
Vancouver
1.
Warsow G, Hübschmann D, Kleinheinz K, Nientiedt C, Heller M, Van Coile L, et al. Genomic features of renal cell carcinoma with venous tumor thrombus. SCIENTIFIC REPORTS. 2018;8.
MLA
Warsow, Gregor, Daniel Hübschmann, Kortine Kleinheinz, et al. “Genomic Features of Renal Cell Carcinoma with Venous Tumor Thrombus.” SCIENTIFIC REPORTS 8 (2018): n. pag. Print.
@article{8561532,
  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 {\textacutedbl}BRCAness{\textacutedbl} in a subset of tumors. These included mutations in genes that confer {\textacutedbl}BRCAness{\textacutedbl}, 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 {\textacutedbl}BRCAness{\textacutedbl} mutational signature AC3 in clear cell RCC. Our findings warrant further pre-clinical experiments and may lead to novel personalized therapies for RCC patients.},
  articleno    = {7477},
  author       = {Warsow, Gregor and H{\"u}bschmann, Daniel and Kleinheinz, Kortine and Nientiedt, Cathleen and Heller, Martina and Van Coile, Laura and Tolstov, Yanis and Trennheuser, Lukas and Wieczorek, Kathrin and Pecqueux, Carine and Gasch, Claudia and Kuru, Timur and Nyarangi-Dix, Joanne and Hatiboglu, Gencay and Teber, Dogu and Perner, Sven and Stenzinger, Albrecht and Roth, Wilfried and Hadaschik, Boris and Pahernik, Sascha and J{\"a}ger, Dirk and Gr{\"u}llich, Carsten and Duensing, Anette and Eils, Roland and Schlesner, Matthias and S{\"u}ltmann, Holger and Hohenfellner, Markus and Duensing, Stefan},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  keyword      = {HOMOLOGY-DIRECTED REPAIR,DOUBLE-STRAND BREAKS,INTRATUMOR HETEROGENEITY,VENA-CAVA,MUTATIONAL PROCESSES,CANCER,SIGNATURES,VARIANTS,BRCA2,HETEROZYGOSITY},
  language     = {eng},
  pages        = {12},
  title        = {Genomic features of renal cell carcinoma with venous tumor thrombus},
  url          = {http://dx.doi.org/10.1038/s41598-018-25544-z},
  volume       = {8},
  year         = {2018},
}

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