Putative drivers of aggressiveness in TCEB1-mutant renal cell carcinoma: An emerging entity with variable clinical course Journal Article
| Authors: | DiNatale, R. G.; Gorelick, A. N.; Makarov, V.; Blum, K. A.; Silagy, A. W.; Freeman, B.; Chowell, D.; Marcon, J.; Mano, R.; Sanchez, A.; Attalla, K.; Weng, S.; Voss, M.; Motzer, R. J.; Russo, P.; Coleman, J. A.; Reuter, V. E.; Chen, Y. B.; Chan, T. A.; Reznik, E.; Tickoo, S. K.; Hakimi, A. A. |
| Article Title: | Putative drivers of aggressiveness in TCEB1-mutant renal cell carcinoma: An emerging entity with variable clinical course |
| Abstract: | Background: TCEB1-mutant renal cell carcinoma (RCC) is a rare variant of RCC with clear-cell features. Owing to its unique morphological and molecular features it has recently been proposed as a separate entity. Initial series suggested an indolent, early-stage phenotype. Here we expand our clinical cohort and describe a more detailed genomic analysis looking for potential drivers of aggressiveness. Design, setting, and participants: We identified five new cases in our institutional sequencing cohort, four of whom were found to have high-stage disease (American Joint Committee on Cancer stage III/IV). Twelve previously reported cases were pooled for comparison purposes (Sato, The Cancer Genome Atlas, TRACERx Renal). Outcome measures and statistical analysis: We used our previously validated pipeline to analyze somatic mutations and copy number alterations (CNAs) in seven tumor samples with available data and estimated the number of cancer cells bearing each somatic mutation. The oncogenic potential of mutations was assessed using OncoKB and two other algorithms. Mann-Whitney U tests were used to evaluate differences in genomic markers between stage groups. Results and limitations: All tumors showed biallelic inactivation of the TCEB1 gene according to a combination of somatic mutation and CNA analyses. Mutations were always found in residues involved in hydrophobic interactions with VHL. We found that high-stage tumors had additional oncogenic mutations (median 1, interquartile range [IQR] 1–1 vs 2, IQR 2–2; median difference 1, 95% confidence interval [CI] 1–1; p = 0.002) and showed whole-genome doubling events. They also seemed to have a higher burden of somatic CNAs (median fraction CNA genome 0.10, IQR 0.10–0.15 vs 0.63, IQR 0.58–0.68), however, this finding did not reach statistical significance (median difference 0.49, 95% CI 0.33–0.63; p = 0.052). Conclusions: TCEB1-mutant RCC can show variable behavior ranging from very indolent to aggressive. Specific molecular events leading to high genomic instability seem to be associated with aggressiveness. This study expands the clinical spectrum of TCEB1-mutant RCC. Patient summary: We present four cases of aggressive TCEB1-mutant renal cell carcinoma, a rare type of kidney cancer. In-depth analysis of the genomes of these tumors revealed certain abnormalities that might explain this aggressive behavior. © 2019 European Association of Urology TCEB1-mutant renal cell carcinoma (RCC) is a rare variant of RCC with a wide spectrum of aggressiveness, ranging from indolent to metastatic. We performed a detailed genomic analysis and uncovered specific molecular events leading to high genomic instability that could to drive this phenotype. © 2019 European Association of Urology |
| Keywords: | adult; clinical article; human tissue; gene mutation; somatic mutation; disease course; bevacizumab; drug withdrawal; unspecified side effect; adjuvant therapy; cancer staging; gene; metastasis; renal cell carcinoma; nephrectomy; genomic instability; gene interaction; pazopanib; gene inactivation; dna mutational analysis; vhl gene; tumor suppressor genes; von hippel lindau protein; copy number variation; hydrophobicity; human; article; tceb1 gene; atezolizumab |
| Journal Title: | European Urology Focus |
| Volume: | 7 |
| Issue: | 2 |
| ISSN: | 2405-4569 |
| Publisher: | Elsevier B.V. |
| Date Published: | 2021-03-01 |
| Start Page: | 381 |
| End Page: | 389 |
| Language: | English |
| DOI: | 10.1016/j.euf.2019.11.013 |
| PUBMED: | 31813809 |
| PROVIDER: | scopus |
| PMCID: | PMC7274909 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 May 2021 -- Source: Scopus |
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