title: Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma.
abstract: BACKGROUND
  Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown.
  
  
  OBJECTIVE
  To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC.
  
  
  METHODS
  Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded.
  
  
  METHODS
  The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]).
  
  
  CONCLUSIONS
  PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p = 0.01 and p = 0.001, respectively). Small tumors (<4 cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p = 0.001). BAP1 mutations tend to occur in Fuhrman grade III-IV tumors (p = 0.052) and are associated with worse CSS (p = 0.01). Clinical outcome data are limited by the number of events.
  
  
  CONCLUSIONS
  Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted.
authors.affiliation: Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: A Ari
authors.initials: AA
authors.lastname: Hakimi
authors.forename: Ying-Bei
authors.initials: YB
authors.lastname: Chen
authors.forename: James
authors.initials: J
authors.lastname: Wren
authors.forename: Mithat
authors.initials: M
authors.lastname: Gonen
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.forename: Shugaku
authors.initials: S
authors.lastname: Takeda
authors.forename: Satish K
authors.initials: SK
authors.lastname: Tickoo
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.forename: Martin H
authors.initials: MH
authors.lastname: Voss
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Coleman
authors.forename: Emily H
authors.initials: EH
authors.lastname: Cheng
authors.forename: Paul
authors.initials: P
authors.lastname: Russo
authors.forename: James J
authors.initials: JJ
authors.lastname: Hsieh
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality / Q000556:secondary*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D016017:Odds Ratio; D010641:Phenotype; D011379:Prognosis; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D047368:Tumor Burden