Renal Cell Carcinoma With Chromosome 6p Amplification Including the TFEB Gene

Abstract

Amplification of chromosome 6p has been implicated in aggressive behavior in several cancers, but has not been characterized in renal cell carcinoma (RCC). We identified 9 renal tumors with amplification of chromosome 6p including the TFEB gene, 3 by fluorescence in situ hybridization, and 6 from the Cancer Genome Atlas (TCGA) databases. Patients' ages were 28 to 78 years (median, 61 y). Most tumors were high stage (7/9 pT3a, 2/9 pN1). Using immunohistochemistry, 2/4 were positive for melanocytic markers and cathepsin K. Novel TFEB fusions were reported by TCGA in 2; however, due to a small composition of fusion transcripts compared with full-length transcripts (0.5/174 and 3.3/132 FPKM), we hypothesize that these represent secondary fusions due to amplification. Five specimens (4 TCGA, 1 fluorescence in situ hybridization) had concurrent chromosome 3p copy number loss or VHL deletion. However, these did not resemble clear cell RCC, had negative carbonic anhydrase IX labeling, lacked VHL mutation, and had papillary or unclassified histology (2/4 had gain of chromosome 7 or 17). One tumor each had somatic FH mutation and SMARCB1 mutation. Chromosome 6p amplification including TFEB is a previously unrecognized cytogenetic alteration in RCC, associated with heterogenous tubulopapillary eosinophilic and clear cell histology. The combined constellation of features does not fit cleanly into an existing tumor category (unclassified), most closely resembling papillary or translocation RCC. The tendency for high tumor stage, varied tubulopapillary morphology, and a subset with melanocytic marker positivity suggests the possibility of a unique tumor type, despite some variation in appearance and genetics.

Comprehensive study of three novel cases of TFEB‐amplified renal cell carcinoma and review of the literature: Evidence for a specific entity with poor outcome

“…Translocation associated with amplification has been described in two other cases . Amplification of TFEB has also recently been described in the absence of translocation: the three novel cases reported here bring to 33 the number of RCCs showing TFEB amplification (Tables ). A review of the literature indicates that most TFEB ‐amplified RCC share several histological features, such as high ISUP grade, papillary, or pseudopapillary architecture and necrotic remodeling.…”

“…However, the role of quantitative genomic alterations co‐existing with TFEB amplification cannot be excluded. Data from the literature are not informative enough as whole genome profiles in TFEB ‐amplified RCC are only available in four cases . Among our three cases, the patient who had the worst outcome had a tumor showing the most complex genomic profile.…”

“…A large‐scale RNA sequencing study identified COL21A1 (6p12.1; coding for the alpha chain of type XXI collagen) and CADM2 (3p12.1; coding for a member of the synaptic cell adhesion molecule 1) as fusion partners of TFEB in two cases of papillary RCC . However, Williamson et al argued that these low‐level fusions could be only secondary rearrangements. In addition, ASPSCR1, one of the TFE3 partners, was suspected to have fused with TFEB in a case of pediatric RCC showing a (6;17)(p21;q24–25) .…”

“…Among the few amplified genes in RCC, recent attention has been drawn to TFEB , a member of the microphtalmia transcription factor (MITF) family that is mainly known for being involved in chromosomal translocations . To our knowledge, to date, 30 cases of high‐level amplification of TFEB in RCCs have been reported (Tables ) . Several of these cases have only been briefly documented at the clinical, histological, and genomic levels.…”

Ancillary studies in fine needle aspiration of the kidney

“…Alternatively, molecular studies (FISH, NGS) can be used to look for deletions of chromosome 3p at the von Hippel Lindau gene in clear cell RCCs, which are typically (though not always) absent from TFE3/TFEB tumors. Instead, TFEB tumors have alterations in chromosome 6p, and TFE3 tumors have alterations in chromosome on Xp11 …”