Abstract 2529: Comprehensive genomic analyses of a case series of bilateral renal cell carcinoma
Authors: Büttner Florian , Meyerhoff Carolin , Kandabarau Siarhei , Winter Stefan , Rausch Steffen , Stenzl Arnulf , Fend Falko , Schroeder Christopher , Bauer Peter , Hoffmann Per , Nöthen Markus M. , Bedke Jens , Schwab Matthias , Schaeffeler Elke 
Published: August 2019

Abstract
Renal cell carcinoma (RCC) accounts for 5% in men and 3% in women of all oncological diagnoses worldwide (Capitanio et al., Eur Urol 2018). In 0.7-4.7% of patients both kidneys are affected by cancer. Although hereditary forms of RCC do exist (VHL disease, hereditary papillary RCC), the majority of bilateral RCC are sporadic. RCC comprises histologically distinct subtypes, and clear cell renal cell carcinoma (ccRCC) constitutes 65-70% of all RCC. Here, we present genomic analyses of three cases with bilateral ccRCC. In particular, we are interested in understanding the origin and evolution of these bilateral tumors. Our study includes bilateral tumors from three patients (P1 - P3). Tumors from patients P1 and P2 are metachronous. Patient P3 showed synchronous bilateral ccRCC, with two distinct tumors in one kidney. Two samples were retrieved per tumor to take account of intratumor heterogeneity. In addition one non-tumor sample was obtained per patient. Paired-end whole exome sequencing (WES) was performed using DNA isolated from all tissue samples. Single nucleotide and short indel variants were called using the Mutect2 software. Additionally, DNA samples were sequenced at ultra-deep coverage (median 1000) using a custom NGS panel comprising 33 genes frequently mutated in RCC to confirm results obtained from WES. The deepSNV method (Gerstung et al., Nat Commun 2012) was used to call somatic mutations from targeted sequencing data. Further, WES data as well as SNP data deriving from microarray analysis (Infinium Global Screening Array-24 v2.0) will be used to reconstruct somatic copy number aberrations for each tumor. We have analyzed relationships between the bilateral tumors by means of somatic mutations from WES data that were shared within and between tumors of a patient. In patient P1 Venn diagram analysis revealed that 1.9% (n=4) of 213 mutations detected in at least in two samples were shared between samples from different tumors. 32% (n=35) of 108 non-unique mutations were shared between tumors from patient P2; 16 mutations were even present in all four samples of P2. 3% (n=9) of 301 non-unique mutations occurred in samples from different tumors in patient P3. None of these mutations was present in all three tumors. Pairwise comparison between tumors of P3 revealed 1.6%, 0.6%, and 2.2% of non-unique mutations overlapping between tumor pairs, respectively. These first observations suggest a common origin of tumors from patient P2, whereas bilateral tumors from patients P1 and P3 seem to be independent events. Data from deep sequencing support these findings in all three cases, e.g. they confirm one of the ubiquitous mutations in P2 that is located in the von Hippel-Lindau gene. In summary, we present a comprehensive genomic analysis of a small case series of bilateral RCC indicating that even a metachronous bilateral RCC can share the common origin.
The work was supported by the Robert Bosch Stiftung, Stuttgart, Germany.
Citation Format: Florian Büttner, Carolin Meyerhoff, Siarhei Kandabarau, Stefan Winter, Steffen Rausch, Arnulf Stenzl, Falko Fend, Christopher Schroeder, Peter Bauer, Per Hoffmann, Markus M. Nöthen, Jens Bedke, Matthias Schwab, Elke Schaeffeler. Comprehensive genomic analyses of a case series of bilateral renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2529.