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

ABSTRACT 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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    • "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.
    Genes Chromosomes and Cancer 08/2015; 54(11). DOI:10.1002/gcc.22277 · 4.04 Impact Factor
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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.
    Journal of Translational Medicine 01/2014; 12(1):10. DOI:10.1186/1479-5876-12-10 · 3.93 Impact Factor
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    • "Furthermore, they affect clinical outcome [9]: del(13q) is associated with a good prognosis whereas del(11q) and del(17p) are associated with a poor prognosis with present-day chemo-immunotherapy approaches. Lower frequency lesions have also been identified involving the MYC locus [25], the short arm of chromosome 8 [23], and lesions probably affecting PIK3CA, NFKB2 and MGA [26,27]. Allele-specific copy number quantification with SNP arrays has also enabled the discovery of frequent copy-neutral loss of heterozygosity in CLL, often resulting in biallelic hits (mutations or epigenetic alterations) in key CLL-related loci, and therefore potentially altering function [24]. "
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) has been consistently at the forefront of genetic research owing to its prevalence and the accessibility of sample material. Recently, genome-wide technologies have been intensively applied to CLL genetics, with remarkable progress. Single nucleotide polymorphism arrays have identified recurring chromosomal aberrations, thereby focusing functional studies on discrete genomic lesions and leading to the first implication of somatic microRNA disruption in cancer. Next-generation sequencing (NGS) has further transformed our understanding of CLL by identifying novel recurrently mutated putative drivers, including the unexpected discovery of somatic mutations affecting spliceosome function. NGS has further enabled in-depth examination of the transcriptional and epigenetic changes in CLL that accompany genetic lesions, and has shed light on how different driver events appear at different stages of disease progression and clonally evolve with relapsed disease. In addition to providing important insights into disease biology, these discoveries have significant translational potential. They enhance prognosis by highlighting specific lesions associated with poor clinical outcomes (for example, driver events such as mutations in the splicing factor subunit gene SF3B1) or with increased clonal heterogeneity (for example, the presence of subclonal driver mutations). Here, we review new genomic discoveries in CLL and discuss their possible implications in the era of precision medicine.
    Genome Medicine 05/2013; 5(5):47. DOI:10.1186/gm451 · 5.34 Impact Factor
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