TY - JOUR
T1 - Next-generation RNA Sequencing–based Biomarker Characterization of Chromophobe Renal Cell Carcinoma and Related Oncocytic Neoplasms[Formula presented]
AU - Skala, Stephanie L.
AU - Wang, Xiaoming
AU - Zhang, Yuping
AU - Mannan, Rahul
AU - Wang, Lisha
AU - Narayanan, Sathiya P.
AU - Vats, Pankaj
AU - Su, Fengyun
AU - Chen, Jin
AU - Cao, Xuhong
AU - Siddiqui, Javed
AU - Argani, Pedram
AU - Cieślik, Marcin P.
AU - Giordano, Thomas J.
AU - Chinnaiyan, Arul M.
AU - Dhanasekaran, Saravana M.
AU - Mehra, Rohit
N1 - Funding Information:
Funding/Support and role of the sponsor: This study was supported by the Michigan Prostate SPORE (2P50CA186786-06), EDRN (1U01CA214170-01), R35 (1R35CA231996-01), and Anatomic Pathology Projects Committee, Department of Pathology, University of Michigan. Research reported in this publication was also supported by the University of Michigan Anatomic Pathology Funding Committee and the National Cancer Institutes of Health under Award Number P30CA046592 by the use of the following Cancer Center Shared Resource(s): Tissue and Molecular Pathology.
Publisher Copyright:
© 2020 European Association of Urology
PY - 2020/7
Y1 - 2020/7
N2 - Background: Renal cell carcinomas (RCCs) are a heterogeneous group of neoplasms. Recent sequencing studies revealed various molecular features associated with histologic RCC subtypes, including chromophobe renal cell carcinoma (ChRCC). Objective: To characterize the gene expression and biomarker signatures associated with ChRCC. Design, setting, and participants: We performed integrative analysis on RNA sequencing data available from 1049 RCC specimens from The Cancer Genome Atlas and in-house studies. Our workflow identified genes relatively enriched in ChRCC, including Forkhead box I1 (FOXI1), Rh family C glycoprotein (RHCG), and LINC01187. We assessed the expression pattern of FOXI1 and RHCG protein by immunohistochemistry (IHC) and LINC01187 mRNA by RNA in situ hybridization (RNA-ISH) in whole tissue sections representing a cohort of 197 RCC cases, including both primary and metastatic tumors. Outcome measurements and statistical analysis: The FOXI1 and RHCG IHC staining, as well as the LINC01187 RNA-ISH staining, was evaluated in each case for intensity, pattern, and localization of expression. Results and limitations: All primary and metastatic classic ChRCCs demonstrated homogeneous positive labeling for FOXI1, RHCG proteins, and LINC01187 transcript. Unclassified RCC with oncocytic features, oncocytoma, and hybrid oncocytic tumor, as well as all but two cases of eosinophilic ChRCC also stained positive. Importantly, metastatic and primary RCC of all other subtypes did not demonstrate any unequivocal staining for FOXI1, RHCG, or LINC01187. In normal kidney, FOXI1, RHCG, and LINC01187 were detected in the distal nephron segment, specifically in intercalated cells. Two cases of eosinophilic ChRCC with focal expression of FOXI1 and LINC01187, and Golgi-like RHCG staining were found to contain MTOR gene mutations upon DNA sequencing. Conclusions: We demonstrate a pipeline for the identification and validation of RCC subtype–specific biomarkers that can aid in the confirmation of cell of origin and may facilitate accurate classification and diagnosis of renal tumors. Patient summary: FOXI1, RHCG, and LINC01187 are lineage-specific signature genes for chromophobe renal cell carcinoma.
AB - Background: Renal cell carcinomas (RCCs) are a heterogeneous group of neoplasms. Recent sequencing studies revealed various molecular features associated with histologic RCC subtypes, including chromophobe renal cell carcinoma (ChRCC). Objective: To characterize the gene expression and biomarker signatures associated with ChRCC. Design, setting, and participants: We performed integrative analysis on RNA sequencing data available from 1049 RCC specimens from The Cancer Genome Atlas and in-house studies. Our workflow identified genes relatively enriched in ChRCC, including Forkhead box I1 (FOXI1), Rh family C glycoprotein (RHCG), and LINC01187. We assessed the expression pattern of FOXI1 and RHCG protein by immunohistochemistry (IHC) and LINC01187 mRNA by RNA in situ hybridization (RNA-ISH) in whole tissue sections representing a cohort of 197 RCC cases, including both primary and metastatic tumors. Outcome measurements and statistical analysis: The FOXI1 and RHCG IHC staining, as well as the LINC01187 RNA-ISH staining, was evaluated in each case for intensity, pattern, and localization of expression. Results and limitations: All primary and metastatic classic ChRCCs demonstrated homogeneous positive labeling for FOXI1, RHCG proteins, and LINC01187 transcript. Unclassified RCC with oncocytic features, oncocytoma, and hybrid oncocytic tumor, as well as all but two cases of eosinophilic ChRCC also stained positive. Importantly, metastatic and primary RCC of all other subtypes did not demonstrate any unequivocal staining for FOXI1, RHCG, or LINC01187. In normal kidney, FOXI1, RHCG, and LINC01187 were detected in the distal nephron segment, specifically in intercalated cells. Two cases of eosinophilic ChRCC with focal expression of FOXI1 and LINC01187, and Golgi-like RHCG staining were found to contain MTOR gene mutations upon DNA sequencing. Conclusions: We demonstrate a pipeline for the identification and validation of RCC subtype–specific biomarkers that can aid in the confirmation of cell of origin and may facilitate accurate classification and diagnosis of renal tumors. Patient summary: FOXI1, RHCG, and LINC01187 are lineage-specific signature genes for chromophobe renal cell carcinoma.
KW - Chromophobe
KW - Classification
KW - Hybrid oncocytic tumor
KW - Immunohistochemistry
KW - Next-generation sequencing
KW - RNA in situ hybridization
KW - Renal cell carcinoma
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U2 - 10.1016/j.eururo.2020.03.003
DO - 10.1016/j.eururo.2020.03.003
M3 - Article
C2 - 32299640
AN - SCOPUS:85083092953
SN - 0302-2838
VL - 78
SP - 63
EP - 74
JO - European Urology
JF - European Urology
IS - 1
ER -