TY - JOUR
T1 - Putative Drivers of Aggressiveness in TCEB1-mutant Renal Cell Carcinoma
T2 - An Emerging Entity with Variable Clinical Course
AU - DiNatale, Renzo G.
AU - Gorelick, Alexander N.
AU - Makarov, Vladimir
AU - Blum, Kyle A.
AU - Silagy, Andrew W.
AU - Freeman, Benjamin
AU - Chowell, Diego
AU - Marcon, Julian
AU - Mano, Roy
AU - Sanchez, Alex
AU - Attalla, Kyrollis
AU - Weng, Stanley
AU - Voss, Martin
AU - Motzer, Robert J.
AU - Russo, Paul
AU - Coleman, Jonathan A.
AU - Reuter, Victor E.
AU - Chen, Ying Bei
AU - Chan, Timothy A.
AU - Reznik, Ed
AU - Tickoo, Satish K.
AU - Hakimi, A. Ari
N1 - Publisher Copyright:
© 2019 European Association of Urology
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - DNA mutational analysis
KW - Genomic instability
KW - Metastasis
KW - Renal cell carcinoma
KW - Tumor suppressor genes
UR - http://www.scopus.com/inward/record.url?scp=85076247957&partnerID=8YFLogxK
U2 - 10.1016/j.euf.2019.11.013
DO - 10.1016/j.euf.2019.11.013
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C2 - 31813809
AN - SCOPUS:85076247957
SN - 2405-4569
VL - 7
SP - 381
EP - 389
JO - European Urology Focus
JF - European Urology Focus
IS - 2
ER -