title: Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas.
abstract: BRAF rearrangements and BRAF V600E point mutations are recurring events in pediatric low-grade gliomas. However, their clinical significance, including possible interactions between these markers and other glioma biomarkers, is unclear. In this study a retrospective cohort of 198 pediatric low-grade gliomas (including 40 treated with adjuvant therapy) was analyzed for BRAF rearrangements, BRAF V600E, p16/CDKN2A deletion, p53 expression, and MIB1 proliferation index. In tumors with BRAF rearrangement, homozygous p16 deletion correlated with shorter progression-free survival (P = .04). A high MIB1 proliferation index trended toward worse response to adjuvant radiotherapy compared to BRAF-rearranged, p16-intact tumors (P = .08). On multivariate analysis, the 2 most consistently powerful independent adverse prognostic markers were midline location (P = .0001) and p16 deletion (P = .03). Tumors with BRAF V600E had a strong trend toward an increased risk for progression (hazard ratio = 2.48, P = .07), whereas those with BRAF rearrangement had a milder trend toward reduced risk (hazard ratio = .54, P = .15). These data suggest that p16 deletion adversely impacts the outcomes of BRAF-driven gliomas, that high proliferation index may be a better marker of progression risk than BRAF, that BRAF rearrangement and BRAF V600E might not necessarily produce comparable outcomes, and that none of these markers is stronger than tumor location in determining prognosis in pediatric low-grade gliomas.
authors.affiliation: Department of Pathology, University of Kentucky, MS-155, 800 Rose Street, Lexington, KY 40536, USA. craig.horbinski@uky.edu
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
authors.forename: Marina N
authors.initials: MN
authors.lastname: Nikiforova
authors.forename: Jill M
authors.initials: JM
authors.lastname: Hagenkord
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
mesh_terms: D000293:Adolescent; D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D015321:Gene Rearrangement; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D055815:Young Adult
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C513496:MIB1 ligase, human; D044767:Ubiquitin-Protein Ligases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf