4.20 MatBA™: A Targeted Oligonucleotide Array for the Assessment of Genomic Copy Number Alterations for Risk Stratification in Chronic Lymphocytic Leukemia

2011 ◽  
Vol 11 ◽  
pp. S231-S232
Author(s):  
Jane Houldsworth ◽  
Asha Guttapalli ◽  
Xiao Jie Yan ◽  
Charles Ma ◽  
Weiyi Chen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Risk Stratification ◽  
Copy Number ◽  
Lymphocytic Leukemia ◽  
Oligonucleotide Array ◽  
Copy Number Alterations ◽  
Genomic Copy Number ◽  
Genomic Copy

scholarly journals Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 3051-3061 ◽  
Author(s):  
Peter Ouillette ◽  
Roxane Collins ◽  
Sajid Shakhan ◽  
Jinghui Li ◽  
Edward Peres ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Outcome ◽  
Copy Number ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Lymphocytic Leukemia ◽  
Copy Number Aberrations ◽  
Genomic Copy Number ◽  
Genomic Complexity ◽  
Genomic Copy

Abstract Genomic aberrations are of predominant importance to the biology and clinical outcome of patients with chronic lymphocytic leukemia (CLL), and FISH-based genomic risk classifications are routinely used in clinical decision making in CLL. One of the known limitations of CLL FISH is the inability to comprehensively interrogate the CLL genome for genomic changes. In an effort at overcoming the existing limitations in CLL genome analysis, we have analyzed high-purity DNA isolated from FACS-sorted CD19+ cells and paired CD3+ or buccal cells from 255 patients with CLL for acquired genomic copy number aberrations (aCNAs) with the use of ultra-high-density Affymetrix SNP 6.0 arrays. Overall, ≥ 2 subchromosomal aCNAs were found in 39% (100 of 255) of all cases analyzed, whereas ≥ 3 subchromosomal aCNAs were detected in 20% (50 of 255) of cases. Subsequently, we have correlated genomic lesion loads (genomic complexity) with the clinical outcome measures time to first therapy and overall survival. With the use of multivariate analyses incorporating the most important prognostic factors in CLL together with SNP 6.0 array–based genomic lesion loads at various thresholds, we identify elevated CLL genomic complexity as an independent and powerful marker for the identification of patients with aggressive CLL and short survival.

Targeted Oligonucleotide Array Assessment of Genomic Copy Number Alterations for Risk Stratification in Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1773-1773
Author(s):  
Jane Houldsworth ◽  
Asha Guttapalli ◽  
Xiao J. Yan ◽  
Charles Ma ◽  
Weiyi Chen ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Copy Number ◽  
Array Cgh ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Copy Number Alterations ◽  
Mutation Status ◽  
Copy Number Changes ◽  
Gain Loss ◽  
Genomic Regions

Abstract Abstract 1773 Risk stratification in chronic lymphocytic leukemia (CLL) is highly desirable and should comprise not only evaluation of clinical features but also molecular prognostic markers. Currently such molecular markers include loss of 17p13, 11q22, 13q14, 6q22, and gain of chromosome 12 as assessed by fluorescence in situ hybridization (FISH) and mutation status of the variable region of the IGH gene (IGHV) by sequencing. In recent years, genome-wide scanning technologies such as array-comparative genomic hybridization (array-CGH) have revealed novel and refined known copy number alterations (CNAs) in the CLL genome. In order to evaluate the potential of array-CGH in prognostication in mature B-cell neoplasms, including CLL, and implement array-CGH in a clinical diagnostic laboratory, a targeted oligonucleotide-based microarray was custom designed to represent genomic regions exhibiting gain/loss in these lymphoid neoplasms. The 4 × 44K formatted array included 2 × 17,348 probes for the 80 selected genomic regions (average resolution of 34kbp), and recommended controls including a 1Mbp genome backbone. DNA extracted from two CLL datasets were submitted to array-CGH using an equimixture of commercially available male/female DNA as a reference. CNAs were detected using Genomics Workbench Lite (Agilent Technologies, Inc.) with the ADM2 algorithm. Analytical sensitivity was assessed by cell line DNA dilution and by FISH (116 specimens) and was 30–40% and 20–25%, respectively. Recurrent CNAs in previously untreated patients, greater than 1.5Mbp in size, were analyzed for association with time to first treatment (TTFT) and overall survival (OS) by the log rank test. Association with IGHV mutation status was tested using the Fisher's two-sided exact test. In both datasets for untreated specimens, unmutated IGHV negatively correlated with both TTFT and OS significantly (p < 0.05). Gain of chromosome 12 was detected in 11–12% of untreated specimens in both datasets and as expected did not associate with outcome. Loss of 13q14 as a sole abnormality (excluding copy number changes arising at known sites of normal variation) was associated with an overall favorable outcome, but specimens with loss of both loci (MIR15A/16-1 and RB1) versus one locus (MIR15A/16-1) did not display significantly different outcomes. As expected loss of 17p13 associated with shorter TTFT and OS, and was observed at higher levels in treated specimens. A similar result was observed for 11q22 loss but not in the second dataset, perhaps due to the relatively short follow-up time. Importantly, four additional copy number changes (gain of 2p, 3q, and 8q, and loss of 8p) were found to associate with shorter TTFT and/or OS, and also occurred at higher frequency in treated specimens. Notably, all but one specimen exhibiting two of these CNAs, were Rai Stage 0-II. After multiple comparisons correction, gain of 2p and 3q, and loss of 8p remained significantly associated with an unfavorable outcome. Gain of 2p25.3-p15 was observed exclusively in unmutated IGHV specimens. Loss of 18p and gain of 17q24 were not considered further for testing due to low frequency or lower frequency in treated specimens (data not shown). Uniquely, these data demonstrate in low-intermediate risk CLL cohorts the prognostic value of genomic gain/loss at multiple sites and support implementation of array-CGH into a clinical setting for risk stratification in CLL where genomic gain or loss of multiple clinically relevant genomic regions can be assessed simultaneously. Dataset 1 Untreated n = 81 TTFT p-value OS p-value Treated n = 38 Dataset 2 n = 169 TTFT p-value OS p-value Treated n = 28 Median TTFT 87.6 mo 24.1 mo Median OS 117.7 mo 37.2 mo Rai Stage     0 25 77     I-II 42 48     III-IV 5 1     na 9 43 Unmutated IGHV 46% (n=80) 0.0003 0.0004 38% (n=163) 0.002 0.044 13q14 loss (sole abnormality) 52.5% 0.038‡ 0.087‡ 33.7% 0.144‡ 0.008‡ MIR15A/16-1, RB1 27.5% 0.77 0.337 11.2% 0.011 1 MIR15A/16-1 25.0% 22.5% 11q22 loss (ATM) 12.3% 0.125 0.009 23.7% 8.3% 0.393 0.977 14.3% 17p13 loss (TP53) 2.5% 0.010 0.012 15.8% 4.7% 0.006 <.0001 10.7% 2p25.3-p15 gain 6.2% 0.002 <.0001 10.5% 3.0% 0.702 0.025 10.7% 8q24 gain 2.5% 0.238 0.014 7.9% 4.1% 0.564 0.007 0.0% 3q26-q27 gain 2.5% <.0001 <.0001 5.3% 3.0% 0.850 <.0001 7.1% 8p23-p21 loss 2.5% 0.002 0.016 10.5% 1.2% 1 <.0001 7.1% Unless otherwise noted, all values associated with shorter times ‡ Associated with longer time na not available Disclosures: Houldsworth: Cancer Genetics, Inc.: Employment. Guttapalli:Cancer Genetics, Inc.: Employment. Ma:Cancer Genetics, Inc.: Employment. Chen:Cancer Genetics, Inc.: Employment. Patil:Cancer Genetics, Inc.: Consultancy.

Genomic copy number alterations in non-small cell lung cancers identified using CBS and MSA

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7695-7695
Author(s):  
M. S. Park ◽  
C. Ma ◽  
M. U. Aziz ◽  
S. Rao ◽  
K. Gold ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Hierarchical Clustering ◽  
Copy Number ◽  
Female Gender ◽  
Small Cell ◽  
Clinical Parameters ◽  
Copy Number Alterations ◽  
Small Cell Lung ◽  
Genomic Copy Number ◽  
Genomic Copy

7695 Background: Lung cancer is the leading cause of cancer death in both men and women with a 5-yr survival rate of 15.5%. Previous studies have begun to characterized genomic copy number alterations of non-small-cell lung CA using array CGH and SNP arrays. We have used aCGH using our 1MB BAC arrays and two algorthims for making copy number alteration (CNA) determinations. We have also pursued the exact copy number gains and losses of several genes using Q-PCR. Methods: Genomic DNA from fresh frozen tumors of 27 patients with NSCLC. We performed aCGH using 1MB Arrays. We used CBS, and MSA to identify regions of CNA. We further pursued several genes of interest (including HRAS, CRK, and CDC42) identified using Q-PCR. Unsupervised hierarchical clustering was performed to look for distinct subgroups. Significant Analysis of Microarrays (SAM) was applied to identify the association between CNAs clinical parameters including tumor subtype, gender, lymph node involvement, tumor stage, and overall survival. Results: 240 regions of amplification and 181 regions of deletions were found, and included all previously published regions implicated in lung cancer. CNAs in > 70% of tumors included amplifications in 1q, 3q, 5p, 6p, 11p, 16q, 20q, and Xq, and deletions in 1p, 8p and 13q. We verified CNAs of HRAS, CRK and CDC42 using Q-PCR. Hierarchical clustering revealed 2 subgroups: one with amplifications in 2q, 4p, 4q, 8q, 21q, 15q, and 16p, and the other with amplifications in 3q, and 5q. These were confirmed by supervised SAM analysis. Using SAM we found that gain of 2q, 4p and 10q, and loss of 16p and 19q were significantly present in adenocarcinomas. (q = 0, FDR = 0%). Gain of 10q, and loss of 6p and 14q were associated with female gender. (q = 0, FDR = 0%). Conclusions: We used aCGH to identify CNAs that characterize non-small cell lung CA tumors with the aim of finding key regions which may harbor important oncogenes and tumor suppressors. Several regions of CNA have been identified, several of which have been associated with clinical parameters. Because much heterogeneity exists in non-small-cell lung tumors, we have demonstrated that clustering analysis is useful in identifying subtypes which may possess prognostic and therapeutic significance. No significant financial relationships to disclose.

Examination of genomic copy number alterations in renal cell carcinoma with sarcomatoid features.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 478-478
Author(s):  
Timothy Ito ◽  
Jianming Pei ◽  
Essel Dulaimi ◽  
Craig Menges ◽  
Philip Abbosh ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Copy Number ◽  
Genetic Alterations ◽  
The Other ◽  
Copy Number Alterations ◽  
Genomic Copy Number ◽  
Genomic Copy ◽  
Sarcomatoid Differentiation

478 Background: Sarcomatoid differentiation is an uncommon histological finding in renal cell carcinoma (RCC) that may develop from any RCC subtype and is associated with a very poor prognosis. The identification of genetic alterations that drive this aggressive phenotype could aid in the development of more effective targeted therapies. In this study, we aimed to identify unique copy number alterations (CNAs) in patients with sarcomatoid RCC when compared to those with other RCC subtypes. Methods: Genomic copy number analysis was performed using single nucleotide polymorphism (SNP)-based microarrays on tissue extracted from the tumors of 80 patients (9 with sarcomatoid features (sRCC), 39 clear cell (ccRCC), 26 papillary (pRCC) and 6 chromophobe RCC (chRCC)) who underwent renal mass excision between 2010 - 2014. Statistical analysis was performed using Kaplan Meier (KM) survival analysis, t-tests and Fisher exact tests where appropriate. Results: sRCC tumors exhibited significantly higher numbers of CNAs when compared to ccRCC, pRCC and chRCC (mean 20.1 vs. 6.6 vs. 7.0 vs. 6.3, respectively; p <0.0001). The most common copy number losses occurred in chromosome arms 1p, 3p, 9q, 15q, 18q, 21q, and 22q, with losses of 9q (88%), 15q (77%), 18q (66%), and 22 (77%) being unique among sRCC tumors when compared to the other 3 histologies. The most common copy number gains were in chromosome arms 1q, 8q, 17q, and 20p/q, with 1q (55%) and 8q (66%) gains unique when compared to the other 3 histologies. Of the sRCC tumors, 3 arose from ccRCC, 2 from pRCC and 4 from unclassified RCC. sRCC was associated with worse survival compared to ccRCC, pRCC and chRCC on KM analysis (p=0.0006), and higher rates of lymph node positivity (77% vs. 3% vs. 12% vs. 0%, respectively; p<0.0001) and metastases (100% vs. 13% vs. 4% vs. 0%, respectively; p<0.0001) on presentation were observed with sRCC. Conclusions: Sarcomatoid differentiation in RCC is associated with a high rate of chromosomal changes with unique copy number alterations including losses of 9q, 15q, 18q and 22q and gains of 1q and 8q. Identification and validation of candidate driver genes or tumor suppressor loci within these chromosomal regions may help identify targets for future therapies.

scholarly journals Genomic Copy Number Alterations in Renal Cell Carcinoma with Sarcomatoid Features

2016 ◽  
Vol 195 (4 Part 1) ◽  
pp. 852-858 ◽  
Author(s):  
Timothy Ito ◽  
Jianming Pei ◽  
Essel Dulaimi ◽  
Craig Menges ◽  
Philip H. Abbosh ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Copy Number ◽  
Copy Number Alterations ◽  
Genomic Copy Number ◽  
Genomic Copy

scholarly journals Investigation of MDM2 Oncogene Copy Number Alterations in Cases of Chronic Lymphocytic Leukemia

2019 ◽  
Vol 36 (2) ◽  
pp. 126-127
Author(s):  
Şule Darbaş ◽  
Çiğdem Aydın ◽  
Ozan Salim ◽  
Sibel Berke Karaüzüm
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Copy Number ◽  
Lymphocytic Leukemia ◽  
Copy Number Alterations
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