|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||Clinical cancer research : an official journal of the American Association for Cancer Research|
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. Clin Cancer Res; 1-12. ©2012 AACR.