Integrative Genomic Analysis Implicates Gain of PIK3CA at 3q26 and MYC at 8q24 in Chronic Lymphocytic Leukemia
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...
Main Authors: | , , , , , , , , , , , , , , , , |
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Format: | Article |
Language: | English |
Published: |
American Association for Cancer Research,
2014-02-21T18:03:41Z.
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Summary: | 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. Dana-Farber Cancer Institute. Center for Cancer Genome Discovery Dana-Farber Cancer Institute (Dana-Farber Strategic Plan Initiative) Dana-Farber Cancer Institute. Center for Cancer Computational Biology Damon Runyon Cancer Research Foundation (CI-38-07) Fonds voor Wetenschappelijk Onderzoek--Vlaanderen Burroughs Wellcome Fund (Career Award at the Scientific Interface) National Institutes of Health (U.S.) (5PO1-CA120964) National Institutes of Health (U.S.) (5P30-CA006516) National Institutes of Health (U.S.) (NIH 5 PO1 CA092625) National Institutes of Health (U.S.) (K23 CA115682) National Institutes of Health (U.S.) (Pioneer Award) Merkin Family Foundation for Stem Cell Research Howard Hughes Medical Institute |
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