|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Brown, JR, Hanna, M, Tesar, B, Werner, L, Pochet, N, Asara, JM, Wang, YE, Dal Cin, P, Fernandes, SM, Thompson, C, MacConaill, L, Wu, CJ, Van de Peer, Y, Correll, M, Regev, A, Neuberg, D, Freedman, AS|
|Journal||Clin Cancer Res|
|Date Published||2012 Jul 15|
|Keywords||Aged, 80 and over, Chromosome Deletion, Chromosome Duplication, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 8, Disease Progression, DNA Copy Number Variations, Female, Gene Expression Profiling, Genes, myc, Genetic Association Studies, Genome, Human, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Phosphatidylinositol 3-Kinases, Polymorphism, Single Nucleotide|
PURPOSE: 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).
EXPERIMENTAL DESIGN: 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.
|Alternate Journal||Clin. Cancer Res.|
|PubMed Central ID||PMC3719990|
|Grant List||5P01-CA120964 / CA / NCI NIH HHS / United States |
P01 CA120964 / CA / NCI NIH HHS / United States
P01 CA092625 / CA / NCI NIH HHS / United States
K23 CA115682 / CA / NCI NIH HHS / United States
5 PO1 CA092625 / CA / NCI NIH HHS / United States
5P30-CA006516 / CA / NCI NIH HHS / United States
R01 CA155010 / CA / NCI NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States