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2015 ; 28
(9
): 1225-35
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Intratumoral morphologic and molecular heterogeneity of rhabdoid renal cell
carcinoma: challenges for personalized therapy
#MMPMID26111976
Singh RR
; Murugan P
; Patel LR
; Voicu H
; Yoo SY
; Majewski T
; Mehrotra M
; Wani K
; Tannir N
; Karam JA
; Jonasch E
; Wood CG
; Creighton CJ
; Medeiros LJ
; Broaddus RR
; Tamboli P
; Baggerly KA
; Aldape KD
; Czerniak B
; Luthra R
; Sircar K
Mod Pathol
2015[Sep]; 28
(9
): 1225-35
PMID26111976
show ga
Rhabdoid histology in clear-cell renal cell carcinoma is associated with a poor
prognosis. The prognosis of patients with clear-cell renal cell carcinoma may
also be influenced by molecular alterations. The aim of this study was to
evaluate the association between histologic features and salient molecular
changes in rhabdoid clear-cell renal cell carcinoma. We macrodissected the
rhabdoid and clear-cell epithelioid components from 12 cases of rhabdoid
clear-cell renal cell carcinoma. We assessed cancer-related mutations from eight
cases using a clinical next-generation exome-sequencing platform. The
transcriptome of rhabdoid clear-cell renal cell carcinoma (n=8) and non-rhabdoid
clear-cell renal cell carcinoma (n=37) was assessed by RNA-seq and gene
expression microarray. VHL (63%) showed identical mutations in all regions from
the same tumor. BAP1 (38%) and PBRM1 (13%) mutations were identified in the
rhabdoid but not in the epithelioid component and were mutually exclusive in 3/3
cases and 1 case, respectively. SETD2 (63%) mutations were discordant between
different histologic regions in 2/5 cases, with mutations called only in the
epithelioid and rhabdoid components, respectively. The transcriptome of rhabdoid
clear-cell renal cell carcinoma was distinct from advanced-stage and high-grade
clear-cell renal cell carcinoma. The diverse histologic components of rhabdoid
clear-cell renal cell carcinoma, however, showed a similar transcriptomic
program, including a similar prognostic gene expression signature. Rhabdoid
clear-cell renal cell carcinoma is transcriptomically distinct and shows a high
rate of SETD2 and BAP1 mutations and a low rate of PBRM1 mutations. Driver
mutations in clear-cell renal cell carcinoma are often discordant across
different morphologic regions, whereas the gene expression program is relatively
stable. Molecular profiling of clear-cell renal cell carcinoma may improve by
assessing for gene expression and sampling tumor foci from different histologic
regions.