Genomic features of renal cell carcinoma with venous tumor thrombus

Gregor Warsow; Daniel Hübschmann; Kortine Kleinheinz; Cathleen Nientiedt; Martina Heller; Laura Van Coile; Yanis Tolstov; Lukas Trennheuser; Kathrin Wieczorek; Carine Pecqueux; Claudia Gasch; Timur Kuru; Joanne Nyarangi-Dix; Gencay Hatiboglu; Dogu Teber; Sven Perner; Albrecht Stenzinger; Wilfried Roth; Boris Hadaschik; Sascha Pahernik; Dirk Jäger; Carsten Grüllich; Anette Duensing; Roland Eils; Matthias Schlesner; Holger Sültmann; Markus Hohenfellner; Stefan Duensing

doi:10.1038/s41598-018-25544-z

Genomic features of renal cell carcinoma with venous tumor thrombus

Gregor Warsow, Daniel Hübschmann, Kortine Kleinheinz, Cathleen Nientiedt, Martina Heller, Laura Van Coile, Yanis Tolstov, Lukas Trennheuser, Kathrin Wieczorek, Carine Pecqueux, Claudia Gasch, Timur Kuru, Joanne Nyarangi-Dix, Gencay Hatiboglu, Dogu Teber, Sven Perner, Albrecht Stenzinger, Wilfried Roth, Boris Hadaschik, Sascha PahernikDirk Jäger, Carsten Grüllich, Anette Duensing, Roland Eils, Matthias Schlesner, Holger Sültmann, Markus Hohenfellner, Stefan Duensing^*

^*Corresponding author for this work

Institute of Pathology

24 Citations (Scopus)

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.

Original language	English
Article number	7477
Journal	Scientific Reports
Volume	8
Issue number	1
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-018-25544-z
Publication status	Published - 01.12.2018

Funding

We would like to thank the tissue bank of the National Center for Tumor Diseases Heidelberg for the procurement of tissue samples. The results shown here are in part based upon data generated by the TCGA Research network: http://cancergenome.nih.gov/. This work was supported by the Wilhelm Sander-Stiftung, the Medical Faculty Heidelberg and an internship by the International Federation of Medical Students Associations (to L.V.C.). D.H. is a member of the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS) and of the M.D./Ph.D.-program of the University of Heidelberg.

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Warsow, G., Hübschmann, D., Kleinheinz, K., Nientiedt, C., Heller, M., Van Coile, L., Tolstov, Y., Trennheuser, L., Wieczorek, K., Pecqueux, C., Gasch, C., Kuru, T., Nyarangi-Dix, J., Hatiboglu, G., Teber, D., Perner, S., Stenzinger, A., Roth, W., Hadaschik, B., ... Duensing, S. (2018). Genomic features of renal cell carcinoma with venous tumor thrombus. Scientific Reports, 8(1), Article 7477. https://doi.org/10.1038/s41598-018-25544-z

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title = "Genomic features of renal cell carcinoma with venous tumor thrombus",

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.",

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Warsow, G, Hübschmann, D, Kleinheinz, K, Nientiedt, C, Heller, M, Van Coile, L, Tolstov, Y, Trennheuser, L, Wieczorek, K, Pecqueux, C, Gasch, C, Kuru, T, Nyarangi-Dix, J, Hatiboglu, G, Teber, D, Perner, S, Stenzinger, A, Roth, W, Hadaschik, B, Pahernik, S, Jäger, D, Grüllich, C, Duensing, A, Eils, R, Schlesner, M, Sültmann, H, Hohenfellner, M & Duensing, S 2018, 'Genomic features of renal cell carcinoma with venous tumor thrombus', Scientific Reports, vol. 8, no. 1, 7477. https://doi.org/10.1038/s41598-018-25544-z

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T1 - Genomic features of renal cell carcinoma with venous tumor thrombus

AU - Warsow, Gregor

AU - Hübschmann, Daniel

AU - Kleinheinz, Kortine

AU - Nientiedt, Cathleen

AU - Heller, Martina

AU - Van Coile, Laura

AU - Tolstov, Yanis

AU - Trennheuser, Lukas

AU - Wieczorek, Kathrin

AU - Pecqueux, Carine

AU - Gasch, Claudia

AU - Kuru, Timur

AU - Nyarangi-Dix, Joanne

AU - Hatiboglu, Gencay

AU - Teber, Dogu

AU - Perner, Sven

AU - Stenzinger, Albrecht

AU - Roth, Wilfried

AU - Hadaschik, Boris

AU - Pahernik, Sascha

AU - Jäger, Dirk

AU - Grüllich, Carsten

AU - Duensing, Anette

AU - Eils, Roland

AU - Schlesner, Matthias

AU - Sültmann, Holger

AU - Hohenfellner, Markus

AU - Duensing, Stefan

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41598-018-25544-z

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C2 - 29748622

AN - SCOPUS:85046934335

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 7477

ER -

Genomic features of renal cell carcinoma with venous tumor thrombus

Abstract

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