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.

CloneSig can jointly infer intra-tumor heterogeneity and mutational signature activity in bulk tumor sequencing data

“…In kidney renal papillary cell carcinoma (KIRP) and kidney renal clear cell carcinoma (KIRC), signature 40 is strongly decreasing, and signature 1 increasing, as reported in [21]. Additionally CloneSig uncovers variations in signature 3 in about half of samples with a signature change in KIRC; activity of signature 3 in KIRC was previously outlined in [28], but undetected in the PCAWG cohort. In Kidney Chromophobe tumors (KICH), CloneSig finds a strong increase of the activity of signature 12, not reproduced in the PCAWG [2, 21], where an increase of signatures 2 and 13 are described.…”

“…In kidney renal papillary cell carcinoma (KIRP) and kidney renal clear cell carcinoma (KIRC), signature 40 is strongly decreasing, and signature 5 increasing. Additionally CloneSig uncovers variations in signature 3 in most samples with a signature change in KIRC; activity of signature 3 in KIRC was previously outlined in [21].…”

“…The resulting list was not satisfactory as it lacked important known patterns; for instance signature 3, associated with homologous recombination repair deficiency was not found to be active in any tumor of the prostate cohort, while signature 3 in prostate cancer is well described in the literature [2, 19, 38]. We therefore completed the signatures present in each cancer type based on the literature [2, 39, 20, 40, 41, 42, 21, 43, 19, 44, 26, 45, 46], and used the resulting matrix in all CloneSig runs on the TCGA. Our curated list of signatures present in each cancer type is provided in Table S4.…”

The Impact of Tumor Eco-Evolution in Renal Cell Carcinoma Sampling

“…Tumor cells reproduce this behavior when a specific subgroup within a community of malignant cells of a tumor decides to invade neighbor tissues or metastasize to other organs far away [16]. The collective acquisition of specific properties of tumor cells composing specific tumor compartments is a well-documented event in most tumors, CCRCC included [22]. This phenomenon applies also for tumor microenvironment.…”

The Impact of Tumor Eco-Evolution in Tumor Sampling

“…Neoplasia encompass a number of complex and largely unknown processes with a metabolic background [12]. [17]. This phenomenon applies also for tumor microenvironment.…”