Juxtaglomerular cell tumor (JxGCT) is a rare type of renal neoplasm demonstrating morphologic overlap with some mesenchymal tumors such as glomus tumor (GT) and solitary fibrous tumor (SFT). Its oncogenic drivers remain elusive, and only a few cases have been analyzed with modern molecular techniques. In prior studies, loss of chromosomes 9 and 11 appeared to be recurrent. Recently, whole-genome analysis identified alterations involving genes of MAPK-RAS pathway in a subset, but no major pathogenic alterations have been discovered in prior whole transcriptome analyses. Considering the limited understanding of the molecular features of JxGCTs, we sought to assess a collaborative series with a multiomic approach to further define the molecular characteristics of this entity. Fifteen tumors morphologically compatible with JxGCTs were evaluated using immunohistochemistry for renin, single-nucleotide polymorphism array (SNP), low-pass whole-genome sequencing, and RNA sequencing (fusion assay). In addition, methylation analysis comparing JxGCT, GT, and SFT was performed. All cases tested with renin (n=11) showed positive staining. Multiple chromosomal abnormalities were identified in all cases analyzed (n=8), with gains of chromosomes 1p, 10, 17, and 19 and losses of chromosomes 9, 11, and 21 being recurrent. A pathogenic HRAS mutation was identified in one case as part of the SNP array analysis. Thirteen tumors were analyzed by RNA sequencing, with 2 revealing in-frame gene fusions: TFG::GPR128 (interpreted as stochastic) and NAB2::STAT6 . The latter, originally diagnosed as JxGCT, was reclassified as SFT and excluded from the series. No fusions were detected in the remaining 11 cases; of note, no case harbored NOTCH fusions previously described in GT. Genomic methylation analysis showed that JxGCT, GT, and SFT form separate clusters, confirming that JxGCT represents a distinct entity (ie, different from GT). The results of our study show that JxGCTs are a distinct tumor type with a recurrent pattern of chromosomal imbalances that may play a role in oncogenesis, with MAPK-RAS pathway activation being likely a driver in a relatively small subset.

Bioptical Laboratory Ltd Plzen Czech Republic

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN

Department of Pathology and Laboratory Medicine Loyola University School of Medicine Maywood IL

Department of Pathology and Molecular Immunology ICBAS School of Medicine and Biomedical Sciences University of Porto Porto Portugal

Department of Pathology CORE Diagnostics and Advanced Medical Research Institute Gurgaon Haryana India

Department of Pathology Faculty of Medicine Charles University

Department of Pathology Indiana University School of Medicine Indianapolis IN

Department of Pathology Portuguese Oncology Institute of Porto R Dr António Bernardino de Almeida

Department of Pathology The University of Alabama at Birmingham Birmingham AL

Department of Pathology University of Southern California Keck School of Medicine Los Angeles CA

Parker H Petit Institute of Bioengineering and Biosciences Georgia Institute of Technology Atlanta GA

Robert J Tomsich Pathology and Laboratory Medicine Institute Cleveland Clinic Cleveland OH

School of Biological Sciences Georgia Institute of Technology

Trinity Health Ann Arbor Ann Arbor MI

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