Integrative genomic analysis implicates gain of PIK3CA at 3q26 and MYC at 8q24 in chronic lymphocytic leukemia.

Clin Cancer Res
Authors
Keywords
Abstract

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.

Year of Publication
2012
Journal
Clin Cancer Res
Volume
18
Issue
14
Pages
3791-802
Date Published
2012 Jul 15
ISSN
1078-0432
URL
DOI
10.1158/1078-0432.CCR-11-2342
PubMed ID
22623730
PubMed Central ID
PMC3719990
Links
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