Genomic features of renal cell carcinoma with venous tumor thrombus

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

doi:10.1038/s41598-018-25544-z

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.

Highlights

Introductionrenal cell carcinoma (RCC) tumor thrombi are subdivided macroscopically according to their consistency into solid or friable
Encouraged by the finding that venous thrombi contain a substantial amount of viable tumor cells, we performed multiregion whole exome sequencing of a total of 37 samples from five consecutive patients with renal cell carcinoma (RCC) and venous tumor thrombus (VTT) (Fig. 2) to directly compare the mutational landscape between the primary tumor and the corresponding VTT
Four patients were diagnosed with clear cell renal cell carcinoma whereas one patient (RCC-VTT-04) had a poorly differentiated type II papillary RCC and, in line with previous reports, mutations in NF2 and SETD233,34

Summary

Introduction

RCC tumor thrombi are subdivided macroscopically according to their consistency into solid or friable The latter has been suggested to be associated with a worse prognosis this notion has recently been challenged[6,7,8]. There is evidence that functional and genomic intratumoral heterogeneity in RCC is shaped by spatial niches[12,13]. To what extent these findings apply to RCC with VTT is currently not known in detail[14]. We provide evidence for homologous recombination defects (“BRCAness”) in a subset of RCCs with VTT, which holds the promise for novel personalized therapeutic interventions in patients with this condition including PARP inhibitors, platinum salts or others[15]

Methods

Results

Conclusion