Integrative Genomic Analysis Implicates Gain of PIK3CA at 3q26 and MYC at 8q24 in Chronic Lymphocytic Leukemia

• Main Authors: Brown, Jennifer R. (Author), Hanna, Megan (Author), Tesar, Bethany (Author), Werner, Lillian (Author), Pochet, Nathalie (Author), Asara, John M. (Author), Wang, Yaoyu E. (Author), dal Cin, Paola (Author), Fernandes, Stacey M. (Author), Thompson, Christina (Author), MacConaill, Laura (Author), Wu, Catherine J. (Author), Van de Peer, Yves (Author), Correll, Mick (Author), Regev, Aviv (Contributor), Neuberg, Donna S. (Author), Freedman, Arnold S. (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor)
• Format: Article
• Language: English
• Published: American Association for Cancer Research, 2014-02-21T18:03:41Z.
• Subjects: Article
• Online Access: Get fulltext

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