Original ArticlesTFEB Expression Profiling in Renal Cell Carcinomas Clinicopathologic CorrelationsGupta, Sounak MBBS, PhD*; Argani, Pedram MD†; Jungbluth, Achim A. MD, PhD*; Chen, Ying-Bei MD, PhD*; Tickoo, Satish K. MD*; Fine, Samson W. MD*; Gopalan, Anuradha MD*; Al-Ahmadie, Hikmat A. MD*; Sirintrapun, Sahussapont J. MD*; Sanchez, Alejandro MD‡,§; Hakimi, Abraham Ari MD‡,§; Mcfarlane, Tiffany MS*; Salazar, Paulo A. MS*; Williamson, Sean R. MD∥; Skala, Stephanie L. MD¶; Mehra, Rohit MD¶; Hes, Ondrej MD#; Antonescu, Cristina R. MD*; Ladanyi, Marc MD*; Arcila, Maria E. MD*; Reuter, Victor E. MD* Author Information Departments of *Pathology ‡Surgery, Urology Service §Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY †Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD ∥Department of Pathology & Laboratory Medicine, Henry Ford Health System, Detroit ¶Department of Pathology, University of Michigan Health System, Ann Arbor, MI #Department of Pathology, University Hospital Plzeň, Charles University, Pilsen, Czech Republic Conflicts of Interest and Source of Funding: Supported in part through NIH/NCI Cancer Center Support grant P30CA008748. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Victor E. Reuter, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (e-mail: [email protected]). The American Journal of Surgical Pathology 43(11):p 1445-1461, November 2019. | DOI: 10.1097/PAS.0000000000001307 Buy Metrics Abstract TFEB is overexpressed in TFEB-rearranged renal cell carcinomas as well as in renal tumors with amplifications of TFEB at 6p21.1. As recent literature suggests that renal tumors with 6p21.1 amplification behave more aggressively than those with rearrangements of TFEB, we compared relative TFEB gene expression in these tumors. This study included 37 TFEB-altered tumors: 15 6p21.1-amplified and 22 TFEB-rearranged (including 5 cases from The Cancer Genome Atlas data set). TFEB status was verified using a combination of fluorescent in situ hybridization (n=27) or comprehensive molecular profiling (n=13) and digital droplet polymerase chain reaction was used to quantify TFEB mRNA expression in 6p21.1-amplified (n=9) and TFEB-rearranged renal tumors (n=19). These results were correlated with TFEB immunohistochemistry. TFEB-altered tumors had higher TFEB expression when normalized to B2M (mean: 168.9%, n=28), compared with non–TFEB-altered controls (mean: 7%, n=18, P=0.005). Interestingly, TFEB expression in tumors with rearrangements (mean: 224.7%, n=19) was higher compared with 6p21.1-amplified tumors (mean: 51.2%, n=9; P=0.06). Of note, classic biphasic morphology was only seen in TFEB-rearranged tumors and when present correlated with 6.8-fold higher TFEB expression (P=0.00004). Our results suggest that 6p21.1 amplified renal tumors show increased TFEB gene expression but not as much as t(6;11) renal tumors. These findings correlate with the less consistent/diffuse expression of downstream markers of TFEB activation (cathepsin K, melan A, HMB45) seen in the amplified neoplasms. This suggests that the aggressive biological behavior of 6p21.1 amplified renal tumors might be secondary to other genes at the 6p21.1 locus that are co-amplified, such as VEGFA and CCND3, or other genetic alterations. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.