title: Integrative genomic analysis implicates gain of PIK3CA at 3q26 and MYC at 8q24 in chronic lymphocytic leukemia.
abstract: OBJECTIVE
  The disease course of chronic lymphocytic leukemia (CLL) varies significantly within cytogenetic groups. We hypothesized that high-resolution genomic analysis of CLL would identify additional recurrent abnormalities associated with short time-to-first therapy (TTFT).
  
  
  METHODS
  We undertook high-resolution genomic analysis of 161 prospectively enrolled CLLs using Affymetrix 6.0 SNP arrays, and integrated analysis of this data set with gene expression profiles.
  
  
  RESULTS
  Copy number analysis (CNA) of nonprogressive CLL reveals a stable genotype, with a median of only 1 somatic CNA per sample. Progressive CLL with 13q deletion was associated with additional somatic CNAs, and a greater number of CNAs was predictive of TTFT. We identified other recurrent CNAs associated with short TTFT: 8q24 amplification focused on the cancer susceptibility locus near MYC in 3.7%; 3q26 amplifications focused on PIK3CA in 5.6%; and 8p deletions in 5% of patients. Sequencing of MYC further identified somatic mutations in two CLLs. We determined which catalytic subunits of phosphoinositide 3-kinase (PI3K) were in active complex with the p85 regulatory subunit and showed enrichment for the α subunit in three CLLs carrying PIK3CA amplification.
  
  
  CONCLUSIONS
  Our findings implicate amplifications of 3q26 focused on PIK3CA and 8q24 focused on MYC in CLL.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Jennifer_Brown@dfci.harvard.edu
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.forename: Megan
authors.initials: M
authors.lastname: Hanna
authors.forename: Bethany
authors.initials: B
authors.lastname: Tesar
authors.forename: Lillian
authors.initials: L
authors.lastname: Werner
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pochet
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Yaoyu E
authors.initials: YE
authors.lastname: Wang
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Fernandes
authors.forename: Christina
authors.initials: C
authors.lastname: Thompson
authors.forename: Laura
authors.initials: L
authors.lastname: Macconaill
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
authors.forename: Yves
authors.initials: Y
authors.lastname: Van de Peer
authors.forename: Mick
authors.initials: M
authors.lastname: Correll
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Freedman
mesh_terms: D000369:Aged, 80 and over; D002872:Chromosome Deletion; D058674:Chromosome Duplication; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D056915:DNA Copy Number Variations / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D016259:Genes, myc / Q000235:genetics*; D056726:Genetic Association Studies; D015894:Genome, Human; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human