title: Intratumoral morphologic and molecular heterogeneity of rhabdoid renal cell carcinoma: challenges for personalized therapy.
abstract: 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.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Singh
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Paari
authors.initials: P
authors.lastname: Murugan
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lalit R
authors.initials: LR
authors.lastname: Patel
authors.affiliation: Department of Medicine and Dan L Duncan Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Horatiu
authors.initials: H
authors.lastname: Voicu
authors.affiliation: Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Suk-Young
authors.initials: SY
authors.lastname: Yoo
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Majewski
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Mehrotra
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Khalida
authors.initials: K
authors.lastname: Wani
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Nizar
authors.initials: N
authors.lastname: Tannir
authors.affiliation: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Karam
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Jonasch
authors.affiliation: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
authors.affiliation: Department of Medicine and Dan L Duncan Center, Baylor College of Medicine, Houston, TX, USA.|Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Pheroze
authors.initials: P
authors.lastname: Tamboli
authors.affiliation: Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Baggerly
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Czerniak
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kanishka
authors.initials: K
authors.lastname: Sircar
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D061346:Laser Capture Microdissection; D020411:Oligonucleotide Array Sequence Analysis; D057285:Precision Medicine; D059467:Transcriptome