title: Renal Cell Carcinoma With Chromosome 6p Amplification Including the TFEB Gene: A Novel Mechanism of Tumor Pathogenesis?
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.
authors.affiliation: *Department of Pathology and Laboratory Medicine †Josephine Ford Cancer Institute ∥Department of Urology, Vattikutti Urology Institute, Henry Ford Health System ‡Department of Pathology, Wayne State University School of Medicine, Detroit #Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI §Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN ¶Department of Environmental Biotechnology, Bharathidasan University, Thiruchirapalli, India.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Williamson
authors.forename: David J
authors.initials: DJ
authors.lastname: Grignon
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.forename: Laura
authors.initials: L
authors.lastname: Favazza
authors.forename: Dibson D
authors.initials: DD
authors.lastname: Gondim
authors.forename: Shannon
authors.initials: S
authors.lastname: Carskadon
authors.forename: Nilesh S
authors.initials: NS
authors.lastname: Gupta
authors.forename: Dhananjay A
authors.initials: DA
authors.lastname: Chitale
authors.forename: Shanker
authors.initials: S
authors.lastname: Kalyana-Sundaram
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
mesh_terms: D000328:Adult; D000368:Aged; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002896:Chromosomes, Human, Pair 6; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D014408:Biomarkers, Tumor; C064972:TFEB protein, human