VEGFA amplification/increased gene copy number and VEGFA mRNA expression in renal cell carcinoma with TFEB gene alterations

Abstract

Amplification of vascular endothelial growth factor A (VEGFA) has been recently reported in TFEB-amplified renal cell carcinomas regardless the level of TFEB amplification. We sought to determine VEGFA amplification by fluorescent in situ hybridization (FISH) and VEGFA mRNA expression by in situ hybridization (RNAscope 2.5) in a series of 10 renal cell carcinomas with TFEB gene alterations, either amplification and/or rearrangement (t(6;11) renal cell carcinoma). TFEB gene rearrangement was demonstrated in eight cases, whereas the remaining two cases showed a high level of TFEB (> 10 copies of fluorescent signals) gene amplification without evidence of rearrangement. Among the eight t(6;11) renal cell carcinomas (TFEB-rearranged cases), one case displayed a high level of TFEB gene amplification and two showed increased TFEB gene copy number (3-4 copies of fluorescent signals). Those three cases behaved aggressively. By FISH, VEGFA was amplified in all three cases with TFEB amplification and increased VEGFA gene copy number was observed in the two aggressive cases t(6;11) renal cell carcinomas with an overlapping increased number of TFEB fluorescent signals. Overall, VEGFA mRNA expression was observed in 8 of 10 cases (80%); of these 8 cases, 3 cases showed high-level TFEB amplification, one case showed TFEB rearrangement with increased TFEB gene copy number, whereas four showed TFEB gene rearrangement without increased copy number. In summary, VEGFA amplification/increased gene copy number and VEGFA mRNA expression occur in TFEB-amplified renal cell carcinoma, but also in a subset of t(6;11) renal cell carcinoma demonstrating aggressive behavior, and in unamplified conventional t(6;11) renal cell carcinoma suggesting VEGFA as potential therapeutic target in these neoplasms even in the absence of TFEB amplification. We finally propose that all the renal tumors showing morphological characteristics suggesting t(6;11) renal cell carcinoma and all unclassified renal cell carcinomas, either high grade or low grade, should immunohistochemically be evaluated for cathepsin K and/or Melan-A and if one of them is positive, tested for TFEB gene alteration and VEGFA gene amplification.

MiT Family Translocation Renal Cell Carcinoma: from the Early Descriptions to the Current Knowledge

“…More recently, renal cell carcinomas with TFEB amplification have been described and appear to be associated with a poor outcome [50,51,52,53,54,55]. TFEB amplification in renal cell carcinoma can occur independently of or in association with TFEB rearrangement [50,55]. TFEB gene rearrangement or amplification increases TFEB expression which causes the subsequent expression of immunohistochemical markers such as cathepsin K, Melan-A, and HMB45 [43].…”

“…Fourth, TFEB amplified renal cell carcinomas typically have a poor outcome while t(6;11) renal cell carcinomas are usually indolent. Of note, it has been demonstrated that renal cell carcinomas showing TFEB amplification harbor concurrent vascular endothelial growth factor A ( VEGFA ) gene amplification [52,55]. This is may be due to the proximity of those two genes, which are both located on the short arm of chromosome 6.…”

A Tale of 2 Morphologies: Diagnostic Pitfalls inTFEB-Associated Renal Cell Carcinomas, Including a NovelNEAT1-TFEBFusion

“…The latter subset portends a distinctly worse prognosis, which is likely attributed to increased expression of these spatially peripheral genes. 11,12,28-30,47…”

“…9,10 The accruing TFEB -translocated family now also includes COL21A1, CADM2, EWSR1, and CLTC (to name a few). 3,9,11-14…”

“…9,10 The accruing TFEB-translocated family now also includes COL21A1, CADM2, EWSR1, and CLTC (to name a few). 3,9,[11][12][13][14] Clinicopathologically, these t (6;11) tumors involving TFEB and MALAT1/α were originally described as arising in younger patients (around the first through third decades), but are now shown to occur as frequently in later adulthood. Importantly-they are overall indolent, in contrast to their more common but prognostically worse TFE3 analogues-although some aggressive cases have been documented.…”