Integrative genomic analysis implicates gain of PIK3CA at 3q26 and MYC at 8q24 in chronic lymphocytic leukemia.
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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
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Journal | Clin Cancer Res
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Volume | 18
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Issue | 14
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Pages | 3791-802
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Date Published | 2012 Jul 15
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ISSN | 1078-0432
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URL | |
DOI | 10.1158/1078-0432.CCR-11-2342
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PubMed ID | 22623730
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PubMed Central ID | PMC3719990
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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
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