TY - JOUR
T1 - TFEB Expression Profiling in Renal Cell Carcinomas
T2 - Clinicopathologic Correlations
AU - Gupta, Sounak
AU - Argani, Pedram
AU - Jungbluth, Achim A.
AU - Chen, Ying Bei
AU - Tickoo, Satish K.
AU - Fine, Samson W.
AU - Gopalan, Anuradha
AU - Al-Ahmadie, Hikmat A.
AU - Sirintrapun, Sahussapont J.
AU - Sanchez, Alejandro
AU - Hakimi, Abraham Ari
AU - Mcfarlane, Tiffany
AU - Salazar, Paulo A.
AU - Williamson, Sean R.
AU - Skala, Stephanie L.
AU - Mehra, Rohit
AU - Hes, Ondrej
AU - Antonescu, Cristina R.
AU - Ladanyi, Marc
AU - Arcila, Maria E.
AU - Reuter, Victor E.
N1 - Funding Information:
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
Publisher Copyright:
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
KW - 6p21.1 amplification
KW - TFEB
KW - rearrangement
KW - renal cell carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85073108556&partnerID=8YFLogxK
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U2 - 10.1097/PAS.0000000000001307
DO - 10.1097/PAS.0000000000001307
M3 - Article
C2 - 31600176
AN - SCOPUS:85073108556
SN - 0147-5185
VL - 43
SP - 1445
EP - 1461
JO - American Journal of Surgical Pathology
JF - American Journal of Surgical Pathology
IS - 11
ER -