TCEB1-mutated renal cell carcinoma: A distinct genomic and morphological subtype Journal Article

Authors: Hakimi, A. A.; Tickoo, S. K.; Jacobsen, A.; Sarungbam, J.; Sfakianos, J. P.; Sato, Y.; Morikawa, T.; Kume, H.; Fukayama, M.; Homma, Y.; Chen, Y. B.; Sankin, A. I.; Mano, R.; Coleman, J. A.; Russo, P.; Ogawa, S.; Sander, C.; Hsieh, J. J.; Reuter, V. E.
Article 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.
Keywords: immunohistochemistry; adult; clinical article; human tissue; protein expression; aged; middle aged; gene mutation; somatic mutation; comparative study; follow up; phenotype; cytology; gene expression; cohort analysis; kidney carcinoma; carbonate dehydratase ix; messenger rna; cytoplasm; gene loss; heterozygosity loss; cytokeratin 7; gene dosage; chromosome 8; tumor gene; hypoxia inducible factor 1alpha; pathologist; gene location; chromosome 7; chromosome 5; human; male; female; priority journal; article; tceb1 gene
Journal Title: Modern Pathology
Volume: 28
Issue: 6
ISSN: 0893-3952
Publisher: Nature Publishing Group  
Date Published: 2015-06-01
Start Page: 845
End Page: 853
Language: English
DOI: 10.1038/modpathol.2015.6
PROVIDER: scopus
PMCID: PMC4449825
PUBMED: 25676555
Notes: Export Date: 2 July 2015 -- Source: Scopus
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MSK Authors
  1. Jonathan Coleman
    184 Coleman
  2. Paul Russo
    446 Russo
  3. Satish K Tickoo
    369 Tickoo
  4. Yingbei Chen
    221 Chen
  5. James J Hsieh
    114 Hsieh
  6. Chris Sander
    196 Sander
  7. Victor Reuter
    899 Reuter
  8. Abraham Ari Hakimi
    129 Hakimi
  9. Alexander Sankin
    12 Sankin
  10. Roy Mano
    21 Mano