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

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Clinical Cancer Research (Impact Factor: 8.72). 05/2012; 18(14):3791-802. DOI: 10.1158/1078-0432.CCR-11-2342
Source: PubMed


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).
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.
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.
Our findings implicate amplifications of 3q26 focused on PIK3CA and 8q24 focused on MYC in CLL.

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Available from: Yves Van de Peer, Sep 28, 2015
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    • "Because chemotherapy depends on TP53 it is mandatory to screen for TP53 alterations before initiation of treatment and to consider different therapeutic approaches like alemtuzumab, idelalisib, navetoclax, or ibrutinib (Pospisilova et al., 2012; Farooqui et al., 2015). Besides 11q and 17p losses, other CNAs reported to confer prognostic value are gains at 2p and 8q and losses at 6q and 8p (Chapiro et al., 2010; Gunnarsson et al., 2010; Brown et al., 2012). Unfortunately, routine FISH testing does not include these regions. "
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) is a common disease with highly variable clinical course. Several recurrent chromosomal alterations are associated with prognosis and may guide risk-adapted therapy. We have developed a targeted genome-wide array to provide a robust tool for ascertaining abnormalities in CLL and to overcome limitations of the 4-marker fluorescence in situ hybridization (FISH). DNA from 180 CLL patients were hybridized to the qChip®Hemo array with a high density of probes covering commonly altered loci in CLL (11q22-q23, 13q14, and 17p13), nine focal regions (2p15-p16.1, 2p24.3, 2q13, 2q36.3-q37.1, 3p21.31, 8q24.21, 9p21.3, 10q24.32, and 18q21.32-q21.33) and two larger regions (6q14.1-q22.31 and 7q31.33-q33). Overall, 86% of the cases presented copy number alterations (CNA) by array. There was a high concordance of array findings with FISH (84% sensitivity, 100% specificity); all discrepancies corresponded to subclonal alterations detected only by FISH. A chromothripsis-like pattern was detected in eight cases. Three showed concomitant shattered 5p with gain of TERT along with isochromosome 17q. Presence of 11q loss was associated with shorter time to first treatment (P = 0.003), whereas 17p loss, increased genomic complexity, and chromothripsis were associated with shorter overall survival (P < 0.001, P = 0.001, and P = 0.02, respectively). In conclusion, we have validated a targeted array for the diagnosis of CLL that accurately detects, in a single experiment, all relevant CNAs, genomic complexity, chromothripsis, copy number neutral loss of heterozygosity, and CNAs not covered by the FISH panel. This test may be used as a practical tool to stratify CLL patients for routine diagnostics or clinical trials. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.
    Full-text · Article · Aug 2015 · Genes Chromosomes and Cancer
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    • "Amplification of genes encoding the catalytic subunits of PIK3CA, PIK3CB, PIK3CD, and PIK3CG has been reported in numerous solid tumors [7]. In lymphomas, PIK3CA has been reported to be amplified in 15/22 (68%) cases of mantle cell lymphoma (MCL) [8], 9/161 (5.6%) cases of chronic lymphocytic leukemia (CLL) [9], and mutated in 1/76 (1.3%) cases of DLBCL [10]; while PIK3CD has been reported to be mutated in 3/73 (4.1%) cases of DLBCL [11]. However, there have been few reports available regarding CNVs or mutations of other PI3K/AKT subunits and their contribution to the activation of the PI3K/AKT pathway in DLBCL. "
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    ABSTRACT: It has been reported that the PI3K/AKT signaling pathway is activated in diffuse large B-cell lymphoma (DLBCL), PI3K constitutive activation plays a crucial role in PI3K/AKT pathway. However, the copy number variations (CNVs) of PI3K subunits on gene level remain unknown in DLBCL. Therefore, the aim of the study is to investigate the CNV of PI3K subunits and their relationship with clinicopathological features exploring the possible mechanism underlying of PI3K activation in DLBCL. CNV of 12 genes in the PI3K/AKT pathway was detected by NanoString nCounter in 60 de novo DLBCLs and 10 reactive hyperplasia specimens as controls. Meanwhile, immunohistochemistry (IHC) was performed to examine the expression of p110alpha, p110beta, p110gamma, p110delta, and pAKT on DLBCL tissue microarrays. All PI3K and AKT subunits, except for PIK3R1, had various CNVs in the form of copy number amplifications and copy number losses. Their rates were in the range of 8.3-20.0%. Of them PIK3CA and PIK3CB gene CNVs were significantly associated with decreased overall survival (P = 0.029 and P = 0.019, respectively). IHC showed that the frequency of strong positive expression of p110alpha, p110beta, p110gamma, and p110delta were 26.7%, 25.0%, 18.3%, and 25.0% respectively, and they were found to be associated with decreased survival (P = 0.022, P = 0.015, P = 0.015, and P = 0.008, respectively). Expression of p110alpha was not only significantly associated with CNVs of PIK3CA (P = 0.002) but also positively correlated with strong positive expression of pAKT (P = 0.026). CNV of PIK3CA is highly associated with aberrant p110alpha protein expression and subsequent activation of PI3K/AKT pathway. CNVs of PIK3CA and PIK3CB, and aberrant protein expression of p110 isoforms are of great important value for predicting inferior prognosis in DLBCL. Frequent CNVs of PI3K/AKT subunits may play an important role in the tumorigenesis of DLBCL.
    Full-text · Article · Jan 2014 · Journal of Translational Medicine
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    • "It is worth noting that both the regions 3q26 and 8q24 contain the oncogenes PIK3CA and MYC, respectively. Although MYC and PIK3CA are frequently amplified in cancer (Beroukhim et al., 2010; Brown et al., 2012; Kolasa et al., 2009), there are several examples within the cBio data sets that the riboproteomic genes within these regions may be amplified without coamplification of the resident oncogene . It is also interesting to note that both MYC and the PI3- kinase signaling pathway represent important regulators of translation themselves. "
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    ABSTRACT: Increasing evidence points to an important role for the ribosome in the regulation of biological processes and as a target for deregulation in disease. Here, we describe a SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry approach to probing mammalian riboproteomes. Using a panel of cell lines, as well as genetic and pharmacological perturbations, we obtained a comparative characterization of the cellular riboproteome. This analysis identified a set of riboproteome components, consisting of a diverse array of proteins with a strong enrichment for RNA-binding proteins. Importantly, this global analysis uncovers a high incidence of genetic alterations to riboproteome components in cancer, with a distinct bias toward genetic amplification. We further validated association with polyribosomes for several riboproteome components and demonstrate that enrichment at the riboproteome can depend on cell type, genetics, or cellular stimulus. Our results have important implications for the understanding of how ribosomes function and provide a platform for uncovering regulators of translation.
    Full-text · Article · Sep 2013 · Cell Reports
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