title: TCEB1-mutated renal cell carcinoma: a distinct genomic and morphological subtype.
abstract: Integrated sequencing analysis identified a group of tumors among clear cell renal cell carcinomas characterized by hotspot mutations in TCEB1 (a gene that contributes to the VHL complex to ubiquitinate hypoxia-inducible factor). We analyzed 11 tumors from two distinct cohorts with TCEB1 mutations along with an expanded cohort to assess whether these should be considered an entity distinct from clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma. All tumors were characterized by hotspot mutations in TCEB1 Y79C/S/F/N or A100P. Morphological and immunohistochemical characteristics of the tumors were assessed by two experienced genitourinary pathologists. Clinical and pathological variables, copy number alterations, mutations, and expression signatures were compared with a cohort of TCEB1 wild-type tumors. All TCEB1-mutated tumors were VHL and PBRM1 wild type and contained distinct copy number profiles including loss of heterozygosity of chromosome 8, the location of TCEB1 (8q21.11). All tumors lacked the clear cell renal cell carcinoma signature 3p loss and contained distinct gene expression signatures. None of the clear cell papillary tumors harbored TCEB1 mutations. Pathologically, all TCEB1-mutated tumors shared characteristic features including thick fibromuscular bands transecting the tumor, pure clear cell cytology frequently with cells showing voluminous cytoplasm, and clear cell renal cell carcinoma-like acinar areas associated with infolding tubular and focally papillary architecture. The presence of voluminous cytoplasm, absence of luminal polarization of tumor nuclei, and lack of extensive cup-like distribution of carbonic anhydrase-IX expression distinguish it from clear cell papillary carcinoma. None of the patients developed metastases at last follow-up (median 48 months). In sum, TCEB1-mutated renal cell carcinoma is a distinct entity with recurrent hotspot mutations, specific copy number alterations, pathway activation, and characteristic morphological features. Further clinical follow-up is needed to determine whether these tumors are more indolent compared with the conventional clear cell renal cell carcinoma.
authors: Department of Surgery - Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY.|Department of Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: A Ari
authors: AA
authors: Hakimi
authors: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: Satish K
authors: SK
authors: Tickoo
authors: Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: Anders
authors: A
authors: Jacobsen
authors: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: Judy
authors: J
authors: Sarungbam
authors: Department of Surgery - Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: John P
authors: JP
authors: Sfakianos
authors: Department of Urology, Graduate School of Medicine, University of Tokyo.|Department of Biology, Graduate School of Medicine, Tokyo.
authors: Yusuke
authors: Y
authors: Sato
authors: Department ofPathology, Graduate School of Medicine, University of Tokyo.
authors: Teppei
authors: T
authors: Morikawa
authors: Department of Urology, Graduate School of Medicine, University of Tokyo.
authors: Haruki
authors: H
authors: Kume
authors: Department ofPathology, Graduate School of Medicine, University of Tokyo.
authors: Masashi
authors: M
authors: Fukayama
authors: Department of Urology, Graduate School of Medicine, University of Tokyo.
authors: Yukio
authors: Y
authors: Homma
authors: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: Ying-Bei
authors: YB
authors: Chen
authors: Department of Surgery - Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: Alexander
authors: A
authors: Sankin
authors: Department of Surgery - Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: Roy
authors: R
authors: Mano
authors: Department of Surgery - Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: Jonathan A
authors: JA
authors: Coleman
authors: Department of Surgery - Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: Paul
authors: P
authors: Russo
authors: Department of Biology, Graduate School of Medicine, Tokyo.
authors: Seishi
authors: S
authors: Ogawa
authors: Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: Chris
authors: C
authors: Sander
authors: Department of Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: James J
authors: JJ
authors: Hsieh
authors: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: Victor E
authors: VE
authors: Reuter
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D000075065:Elongin; D005260:Female; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C000616395:ELOC protein, human; D000075065:Elongin; D014157:Transcription Factors