title: An integrated analysis of germline and somatic, genetic and epigenetic alterations at 9p21.3 in glioblastoma.
abstract: BACKGROUND
  Glioblastoma multiforme (GBM) is the most prevalent and deadly brain tumor. A variety of germline and somatic, genetic and epigenetic alterations at 9p21.3, which encode CDKN2A/CDKN2B tumor suppressor genes, have been isolatedly reported to be associated with GBM risk and prognosis.
  
  
  METHODS
  To obtain a comprehensive view of these events, we leveraged the wide-spectrum GBM data available from The Cancer Genome Atlas project and performed an integrated analysis by systematically evaluating 9p21.3-related germline single-nucleotide polymorphisms, somatic copy number alterations (CNAs), DNA methylation, and microRNAs (miRNAs) with regard to CDKN2A/CDKN2B expression and patient prognosis in GBM.
  
  
  RESULTS
  Our multivariate analysis indicated that expression of CDKN2A and CDKN2B was both strongly affected by CNAs (P = 1.00 × 10(-4) and 2.37 × 10(-14)). The miRNAs hsa-mir-126, hsa-mir-517a, and hsa-mir-125b exhibited significant negative correlations with CDKN2A expression (P = 0.003, 0.041, and 0.050). Survival analysis showed that complete 9p21.3 loss and low CDKN2B expression were associated with worse prognosis for both tumor progression/recurrence-free survival (P = .041 and .019) and patient overall survival (P = .043 and .021) after adjustment for age and treatment, and that higher methylation at cg17449661 predicted poorer overall survival (P = .048).
  
  
  CONCLUSIONS
  Representing one of the first attempts to systematically integrate various levels of alterations associated with the often complex cancer genomes and phenotypes, our study provided a holistic view and a mechanistic explanation over the functional connections of multiple 9p21.3-related events in GBM, as well as clinically useful biomarker information for predicting disease outcomes.
authors.affiliation: Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Feng
authors.forename: Seong-Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Wennuan
authors.initials: W
authors.lastname: Liu
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Michael
authors.initials: M
authors.lastname: Berens
authors.forename: Jielin
authors.initials: J
authors.lastname: Sun
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D002899:Chromosomes, Human, Pair 9; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D005260:Female; D019942:Genes, p16; D005854:Germ Cells; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D008297:Male; D035683:MicroRNAs; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis
chemical_list: D035683:MicroRNAs