PMID- 31813809
OWN - NLM
STAT- MEDLINE
DCOM- 20220328
LR  - 20220328
IS  - 2405-4569 (Electronic)
IS  - 2405-4569 (Linking)
VI  - 7
IP  - 2
DP  - 2021 Mar
TI  - Putative Drivers of Aggressiveness in TCEB1-mutant Renal Cell Carcinoma: An 
      Emerging Entity with Variable Clinical Course.
PG  - 381-389
LID - S2405-4569(19)30354-2 [pii]
LID - 10.1016/j.euf.2019.11.013 [doi]
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.
CI  - Copyright (c) 2019 European Association of Urology. Published by Elsevier B.V. All 
      rights reserved.
FAU - DiNatale, Renzo G
AU  - DiNatale RG
AD  - Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 
      New York, NY, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan 
      Kettering Cancer Center, New York, NY, USA; Computational Oncology Service, 
      Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer 
      Center, New York, NY, USA.
FAU - Gorelick, Alexander N
AU  - Gorelick AN
AD  - Computational Oncology Service, Department of Epidemiology & Biostatistics, 
      Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Molecular 
      Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
FAU - Makarov, Vladimir
AU  - Makarov V
AD  - Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer 
      Center, New York, NY, USA.
FAU - Blum, Kyle A
AU  - Blum KA
AD  - Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 
      New York, NY, USA.
FAU - Silagy, Andrew W
AU  - Silagy AW
AD  - Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 
      New York, NY, USA.
FAU - Freeman, Benjamin
AU  - Freeman B
AD  - Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 
      New York, NY, USA.
FAU - Chowell, Diego
AU  - Chowell D
AD  - Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer 
      Center, New York, NY, USA.
FAU - Marcon, Julian
AU  - Marcon J
AD  - Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 
      New York, NY, USA.
FAU - Mano, Roy
AU  - Mano R
AD  - Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 
      New York, NY, USA.
FAU - Sanchez, Alex
AU  - Sanchez A
AD  - Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 
      New York, NY, USA.
FAU - Attalla, Kyrollis
AU  - Attalla K
AD  - Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 
      New York, NY, USA.
FAU - Weng, Stanley
AU  - Weng S
AD  - Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 
      New York, NY, USA.
FAU - Voss, Martin
AU  - Voss M
AD  - Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering 
      Cancer Center, New York, NY, USA.
FAU - Motzer, Robert J
AU  - Motzer RJ
AD  - Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering 
      Cancer Center, New York, NY, USA.
FAU - Russo, Paul
AU  - Russo P
AD  - Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 
      New York, NY, USA.
FAU - Coleman, Jonathan A
AU  - Coleman JA
AD  - Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 
      New York, NY, USA.
FAU - Reuter, Victor E
AU  - Reuter VE
AD  - Pathology Department, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
FAU - Chen, Ying-Bei
AU  - Chen YB
AD  - Pathology Department, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
FAU - Chan, Timothy A
AU  - Chan TA
AD  - Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer 
      Center, New York, NY, USA.
FAU - Reznik, Ed
AU  - Reznik E
AD  - Computational Oncology Service, Department of Epidemiology & Biostatistics, 
      Memorial Sloan Kettering Cancer Center, New York, NY, USA.
FAU - Tickoo, Satish K
AU  - Tickoo SK
AD  - Pathology Department, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 
      Electronic address: tickoos@mskcc.org.
FAU - Hakimi, A Ari
AU  - Hakimi AA
AD  - Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 
      New York, NY, USA. Electronic address: hakimia@mskcc.org.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - T32 CA082088/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20191206
PL  - Netherlands
TA  - Eur Urol Focus
JT  - European urology focus
JID - 101665661
RN  - 0 (Biomarkers, Tumor)
SB  - IM
MH  - Biomarkers, Tumor/genetics
MH  - Carcinoma, Renal Cell/*genetics/pathology
MH  - DNA Copy Number Variations
MH  - Genomics
MH  - Humans
MH  - Kidney Neoplasms/*genetics/pathology
MH  - Sequence Analysis, DNA
PMC - PMC7274909
MID - NIHMS1546117
OTO - NOTNLM
OT  - DNA mutational analysis
OT  - Genomic instability
OT  - Metastasis
OT  - Renal cell carcinoma
OT  - Tumor suppressor genes
EDAT- 2019/12/10 06:00
MHDA- 2022/03/29 06:00
PMCR- 2022/03/01
CRDT- 2019/12/10 06:00
PHST- 2019/08/20 00:00 [received]
PHST- 2019/11/06 00:00 [revised]
PHST- 2019/11/19 00:00 [accepted]
PHST- 2019/12/10 06:00 [pubmed]
PHST- 2022/03/29 06:00 [medline]
PHST- 2019/12/10 06:00 [entrez]
PHST- 2022/03/01 00:00 [pmc-release]
AID - S2405-4569(19)30354-2 [pii]
AID - 10.1016/j.euf.2019.11.013 [doi]
PST - ppublish
SO  - Eur Urol Focus. 2021 Mar;7(2):381-389. doi: 10.1016/j.euf.2019.11.013. Epub 2019 
      Dec 6.