PMID- 37088333
OWN - NLM
STAT- MEDLINE
DCOM- 20230821
LR  - 20230908
IS  - 1530-0285 (Electronic)
IS  - 0893-3952 (Linking)
VI  - 36
IP  - 8
DP  - 2023 Aug
TI  - Biallelic ELOC-Inactivated Renal Cell Carcinoma: Molecular Features Supporting 
      Classification as a Distinct Entity.
PG  - 100194
LID - S0893-3952(23)00099-6 [pii]
LID - 10.1016/j.modpat.2023.100194 [doi]
AB  - Approximately 70% of clear cell renal cell carcinoma (ccRCC) is characterized by 
      the biallelic inactivation of von Hippel-Lindau (VHL) on chromosome 3p. 
      ELOC-mutated (Elongin C-mutated) renal cell carcinoma containing biallelic ELOC 
      inactivations with chromosome 8q deletions is considered a novel subtype of renal 
      cancer possessing a morphologic overlap with ccRCC, renal cell carcinoma (RCC) 
      with fibromyomatous stroma exhibiting Tuberous Sclerosis Complex (TSC)/mammalian 
      Target of Rapamycin (mTOR) mutations, and clear cell papillary tumor. However, 
      the frequency and consequences of ELOC alterations in wild-type VHL and mutated 
      VHL RCC are unclear. In this study, we characterize 123 renal tumors with clear 
      cell morphology and known VHL mutation status to assess the morphologic and 
      molecular consequences of ELOC inactivation. Using OncoScan and whole-exome 
      sequencing, we identify 18 ELOC-deleted RCCs, 3 of which contain ELOC mutations 
      resulting in the biallelic inactivation of ELOC. Biallelic ELOC and biallelic VHL 
      aberrations were mutually exclusive; however, 2 ELOC-mutated RCCs showed 
      monoallelic VHL alterations. Furthermore, no mutations in TSC1, TSC2, or mTOR 
      were identified in ELOC-mutated RCC with biallelic ELOC inactivation. Using High 
      Ambiguity Driven biomolecular DOCKing, we report a novel ELOC variant containing 
      a duplication event disrupting ELOC-VHL interaction alongside the frequently seen 
      Y79C alteration. Using hyper reaction monitoring mass spectrometry, we show RCCs 
      with biallelic ELOC alterations have significantly reduced ELOC expression but 
      similar carbonic anhydrase 9 and vascular endothelial growth factor A expression 
      compared with classical ccRCC with biallelic VHL inactivation. The absence of 
      biallelic VHL and TSC1, TSC2, or mTOR inactivation in RCC with biallelic ELOC 
      inactivation (ELOC mutation in combination with ELOC deletions on chromosome 8q) 
      supports the notion of a novel, molecularly defined tumor entity.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Batavia, Aashil A
AU  - Batavia AA
AD  - Department of Pathology and Molecular Pathology, University Hospital Zurich, 
      University of Zurich, Zurich, Switzerland; Department of Biosystems Science and 
      Engineering, Eidgenossische Technische Hochschule Zurich, Basel, Switzerland; 
      Swiss Institute of Bioinformatics, Basel, Switzerland.
FAU - Rutishauser, Dorothea
AU  - Rutishauser D
AD  - Department of Pathology and Molecular Pathology, University Hospital Zurich, 
      University of Zurich, Zurich, Switzerland.
FAU - Sobottka, Bettina
AU  - Sobottka B
AD  - Department of Pathology and Molecular Pathology, University Hospital Zurich, 
      University of Zurich, Zurich, Switzerland.
FAU - Schraml, Peter
AU  - Schraml P
AD  - Department of Pathology and Molecular Pathology, University Hospital Zurich, 
      University of Zurich, Zurich, Switzerland.
FAU - Beerenwinkel, Niko
AU  - Beerenwinkel N
AD  - Department of Biosystems Science and Engineering, Eidgenossische Technische 
      Hochschule Zurich, Basel, Switzerland; Swiss Institute of Bioinformatics, Basel, 
      Switzerland.
FAU - Moch, Holger
AU  - Moch H
AD  - Department of Pathology and Molecular Pathology, University Hospital Zurich, 
      University of Zurich, Zurich, Switzerland. Electronic address: 
      holger.moch@usz.ch.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230423
PL  - United States
TA  - Mod Pathol
JT  - Modern pathology : an official journal of the United States and Canadian Academy 
      of Pathology, Inc
JID - 8806605
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Elongin)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Humans
MH  - *Carcinoma, Renal Cell/pathology
MH  - Vascular Endothelial Growth Factor A
MH  - Elongin/genetics
MH  - Von Hippel-Lindau Tumor Suppressor Protein/genetics
MH  - *Kidney Neoplasms/genetics/pathology
MH  - TOR Serine-Threonine Kinases
OTO - NOTNLM
OT  - VHL gene
OT  - renal cell carcinoma
OT  - translational research
OT  - tumor classification
EDAT- 2023/04/24 00:41
MHDA- 2023/08/21 06:43
CRDT- 2023/04/23 19:32
PHST- 2022/10/19 00:00 [received]
PHST- 2023/03/28 00:00 [revised]
PHST- 2023/04/16 00:00 [accepted]
PHST- 2023/08/21 06:43 [medline]
PHST- 2023/04/24 00:41 [pubmed]
PHST- 2023/04/23 19:32 [entrez]
AID - S0893-3952(23)00099-6 [pii]
AID - 10.1016/j.modpat.2023.100194 [doi]
PST - ppublish
SO  - Mod Pathol. 2023 Aug;36(8):100194. doi: 10.1016/j.modpat.2023.100194. Epub 2023 
      Apr 23.