Next-generation RNA Sequencing-based Biomarker Characterization of Chromophobe Renal Cell Carcinoma and Related Oncocytic Neoplasms.

Abstract:

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.

journal_name

Eur Urol

journal_title

European urology

authors

Skala SL,Wang X,Zhang Y,Mannan R,Wang L,Narayanan SP,Vats P,Su F,Chen J,Cao X,Siddiqui J,Argani P,Cieślik MP,Giordano TJ,Chinnaiyan AM,Dhanasekaran SM,Mehra R

doi

10.1016/j.eururo.2020.03.003

subject

Has Abstract

pub_date

2020-07-01 00:00:00

pages

63-74

issue

1

eissn

0302-2838

issn

1873-7560

pii

S0302-2838(20)30144-5

journal_volume

78

pub_type

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