Development of a DNA Methylation-Based Diagnostic Signature to Distinguish Benign Oncocytoma From Renal Cell Carcinoma.

A challenge in the diagnosis of renal cell carcinoma (RCC) is to distinguish chromophobe RCC (chRCC) from benign renal oncocytoma, because these tumor types are histologically and morphologically similar, yet they require different clinical management. Molecular biomarkers could provide a way of distinguishing oncocytoma from chRCC, which could prevent unnecessary treatment of oncocytoma. Such biomarkers could also be applied to preoperative biopsy specimens such as needle core biopsy specimens, to avoid unnecessary surgery of oncocytoma.

We profiled DNA methylation in fresh-frozen oncocytoma and chRCC tumors and adjacent normal tissue and used machine learning to identify a signature of differentially methylated cytosine-phosphate-guanine sites (CpGs) that robustly distinguish oncocytoma from chRCC.

Unsupervised clustering of Stanford and preexisting RCC data from The Cancer Genome Atlas (TCGA) revealed that of all RCC subtypes, oncocytoma is most similar to chRCC. Unexpectedly, however, oncocytoma features more extensive, overall abnormal methylation than does chRCC. We identified 79 CpGs with large methylation differences between oncocytoma and chRCC. A diagnostic model trained on 30 CpGs could distinguish oncocytoma from chRCC in 10-fold cross-validation (area under the receiver operating curve [AUC], 0.96 (95% CI, 0.88 to 1.00)) and could distinguish TCGA chRCCs from an independent set of oncocytomas from a previous study (AUC, 0.87). This signature also separated oncocytoma from other RCC subtypes and normal tissue, revealing it as a standalone diagnostic biomarker for oncocytoma.

This CpG signature could be developed as a clinical biomarker to support differential diagnosis of oncocytoma and chRCC in surgical samples. With improved biopsy techniques, this signature could be applied to preoperative biopsy specimens.

JCO precision oncology. 2020 Sep 28*** epublish ***

Kevin Brennan, Thomas J Metzner, Chia-Sui Kao, Charlie E Massie, Grant D Stewart, Robert W Haile, James D Brooks, Megan P Hitchins, John T Leppert, Olivier Gevaert

Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA., Department of Urology, Stanford University School of Medicine, Stanford University, Stanford, CA., Department of Clinical Pathology, Stanford University Medical Center, Stanford, CA., Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, United Kingdom., Department of Surgery, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom., Research Center for Health Equity, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA., Division of Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA.