TFEB Expression Profiling in Renal Cell Carcinomas: Clinicopathologic Correlations

Sounak Gupta, Pedram Argani, Achim A. Jungbluth, Ying Bei Chen, Satish K. Tickoo, Samson W. Fine, Anuradha Gopalan, Hikmat A. Al-Ahmadie, Sahussapont J. Sirintrapun, Alejandro Sanchez, Abraham Ari Hakimi, Tiffany Mcfarlane, Paulo A. Salazar, Sean R. Williamson, Stephanie L. Skala, Rohit Mehra, Ondrej Hes, Cristina R. Antonescu, Marc Ladanyi, Maria E. ArcilaVictor E. Reuter

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1445-1461
Number of pages17
JournalAmerican Journal of Surgical Pathology
Volume43
Issue number11
DOIs
StatePublished - Nov 1 2019

Keywords

  • 6p21.1 amplification
  • TFEB
  • rearrangement
  • renal cell carcinoma

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

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