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.

Acquired Genomic Copy Number Aberrations and Survival In CLL

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1713-1713 ◽  
Author(s):  
Sami Malek ◽  
Brian Parkin ◽  
Edward M. Peres ◽  
Moshe Talpaz ◽  
Mark S. Kaminski ◽  
...  
Keyword(s):  
Overall Survival ◽  
Copy Number ◽  
Conflicts Of Interest ◽  
Similar Data ◽  
Exon 2 ◽  
Copy Number Aberrations ◽  
Genomic Copy Number ◽  
Genomic Complexity ◽  
Genomic Copy ◽  
Diagnosis Date

Abstract Abstract 1713 Genomic aberrations like 17p and 11q deletions and mutations in p53 affect survival outcome in CLL. To further our understanding of the anatomy and clinical importance of various acquired genomic copy number aberrations (aCNA) in CLL, we have generated SNP 6.0 array-based genomic profiling data of DNA from sorted CD19+/CD3+ cells from 256 CLL patients, of which 201 were untreated and 55 relapsed (median number of prior therapies 1) at study enrollment. Acquired CNAs were detected using visual inspection of paired (CD19+: tumor/CD3+: normal reference DNA) genomic copy number heatmap displays using the validated software tool dChipSNP. This analytical approach is conservative and has been previously externally validated using FISH for other tumor types and lesions > 0.2 Mb. The range of aCNA for all cases was 0–22 lesions, most of which were sub-chromosomal deletions. We did not detect a sub-chromosomal aCNA in 72/256=28% of the cases even at this ultra-high resolution, suggesting that sub- chromosomal aCNA are not involved in the pathogenesis of this CLL subset. Three or more sub-chromosomal lesions were found in 50/256=20% of all cases analyzed; this is likely a low estimate of the true frequency of this genomic CLL type given the aggressive clinical behavior. Of the 50 cases with ≥3 sub-chromosomal lesions, 26 harbored somatically acquired p53 exon 2–10 mutations (26/50=52%). Next we determined the prognostic importance of various established and novel biomarkers on the clinical endpoint overall survival (OS; alternatively computed using either the CLL diagnosis date or the trial enrollment date as the reference date). For previously untreated patients (N=201) and for the OS analysis based on the diagnosis date and the date of death, OS was 84 months for p53 mutated cases (N=24), 94 months for 17p cases (N=16), 116 months for 11q cases (N=14), 237 months for ZAP70+ cases (N=85), 174 months for IgVH unmutated cases (N=82) and 167, 90 and 52 months for ≥2 (N=68), ≥3 (N=31) or ≥4 (N=19) aCNA based on SNP 6.0 array profiling, respectively. For all patients (N=256) and for the OS analysis based on the diagnosis date and date of death, OS was 96 months for p53 mutated cases (N=36), 91 months for 17p cases (N=25), 123 months for 11q cases (N=25), 139 months for ZAP70+ cases (N=123), 123 months for IgVH unmutated cases (N=116) and 144, 108 and 77 months for ≥2 (N=100), ≥3 (N=50) or ≥4 (N=33) aCNA based on SNP 6.0 array profiling, respectively. Furthermore, CLL patients with wild type p53 exons 2–10 and SNP 6.0 array-based genomic lesion loads of 2 lesions or more had significantly (all p<0.05) shorter OS than the corresponding lower genomic complexity cases. Finally, similar data were obtained if the CLL trial enrollment date as opposed to the CLL diagnosis date was used to compute OS. We proceeded with multivariate analyses including various base variables (del17p, del11q, p53 exon 2–10 mutations, ZAP70 status, IgVH status) in the models as well as SNP 6.0 array-based genomic complexity at various thresholds. Furthermore, models were based on previously untreated patients only or alternatively on all patients. Finally, models were based on the CLL diagnosis date or alternatively the CLL trial enrollment date as the reference date for OS computations. Importantly, for all models, genomic complexity emerged as an independent and dominant predictor of short OS. For instance, for previously untreated patients (N=192) and OS based on the diagnosis date in CLL, the hazard ratio (HR) for short OS for genomic complexity ≥3 lesions was 3.95 (CI=1.12-13.95; p=0.03) when controlling for ZAP70 status HR=0.68 (CI=0.25-1.89; p=0.46), IgVH unmutated HR=2.64 (CI=0.91-7.68; p=0.07) and p53 exon 2–10 mutations HR=1.95 (CI=0.51-7.43; p=0.32). For all patients (N=247) the corresponding results were: genomic complexity ≥3 lesions HR=3.57 (CI=1.72-7.44; p<0.01) when controlling for ZAP70 status HR=1.55 (CI=0.74-3.23; p=0.23), IgVH unmutated HR=2.93 (CI=1.39-6.21; p<0.01) and p53 exon 2–10 mutations HR=0.9 (CI=0.4-2.03; p=0.79) with OS based on the diagnosis date. Similar results were obtained when controlling for 17p or 11q status. In summary, this data demonstrates that a subgroup of CLL patients with elevated genomic complexity has poor overall survival (akin to patients with p53 mutations) and thus should be specifically targeted for novel therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.

Detailed Molecular Analysis of Patients with Chronic Lymphocytic Leukemia Carrying 17p Deletions Reveals Concurrent Abnormalities with Prognostic Impact

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4577-4577
Author(s):  
Julio Delgado ◽  
Itziar Salaverría ◽  
Eriong Lee ◽  
Laura Jiménez ◽  
Alba Navarro ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Chronic Lymphocytic Leukemia ◽  
Copy Number ◽  
Prognostic Value ◽  
De Novo ◽  
Lymphocytic Leukemia ◽  
Complex Karyotype ◽  
Tp53 Mutations ◽  
Genomic Complexity ◽  
Allelic Burden

Abstract Abstract 4577 Patients with chronic lymphocytic leukemia (CLL) whose tumor cells harbor 17p deletions (17p-) by fluorescent in-situ hybridization (FISH) or chromosome banding analysis (CBA) are considered to have a poor survival. The disease is usually refractory to conventional chemotherapy and alternative therapeutic approaches are generally recommended. There is, however, a degree of clinical heterogeneity within 17p- CLL patients, as a significant proportion of them remain asymptomatic for prolonged periods of time. The aim of this study was to determine the prognostic value of concomitant molecular abnormalities in patients with 17p- CLL. Clinical and laboratory data were collected from 76 patients with 17p- CLL, detected either at diagnosis (de novo deletions, 39 patients) or over the course of the disease (acquired deletions, 37 patients). The cut-off used to define a positive FISH result was 10%, and complex karyotype was defined as the presence of 3 or more aberrations by CBA. We performed Sanger sequencing of IGHV, TP53 (exons 4–9), NOTCH1 (exon 34) and SF3B1 (exons 14–18), as well as high resolution copy number analysis using a SNP-array platform (CN-SNP). Both CBA/FISH and molecular studies were performed on samples drawn on the same date. Main biological characteristics, including CD38 and ZAP-70 expression or beta2-microglobulin (B2M), were also recorded. We evaluated the impact of these variables on time to first treatment (TTFT) and overall survival (OS) from sampling. TTFT was only evaluated in patients with de novo 17p-, and OS was evaluated in the whole cohort. Optimal cut-offs for FISH, B2M and copy number aberrations (CNAs) were calculated using maximally selected rank statistics, and were ≥25%, ≥3.5 mg/dl and ≥3, respectively (maxstat package, R, version 2.15.0). TP53 mutations were detected in 28/60 (47%) patients, and were more frequent in patients with ≥25% 17p- cells by FISH (64% vs 32%, p=0.029). CN-SNP confirmed 17p losses in only 19/68 (28%) patients and 90% of them also had concurrent TP53 mutations. 17p- by CN-SNP were mostly detected in patients with ≥25% 17p- cells by FISH [11/16 (69%)], compared to 6/49 (12%) patients with <25% cells (p<0.001). Median CNAs was 2 (range, 0–21) and was significantly higher in patients with ≥25% 17p- cells by FISH (median 3) compared to those patients with a lower allelic burden (median 1, p=0.017). Median CNAs were also higher in patients with 17p- by CN-SNP compared to those without 17p- by CN-SNP (3 vs 1, p<0.001). NOTCH1 and SF3B1 mutations were found in 8/42 (19%) and 1/20 (5%) patients, respectively. Variables predictive of a shorter TTFT in patients with de novo 17p- were unmutated IGHV genes (p=0.037), positive CD38 expression (p=0.002), positive ZAP-70 expression (p=0.010), complex karyotype by CBA (p=0.043), and ≥3 CNAs by SNP arrays (p=0.002). Multivariate analysis revealed that the presence of ≥3 CNAs was the only variable with independent prognostic value in terms of TTFT (hazard ratio [HR] 5.8, 95% confidence interval [CI] 2.0–16.7, p=0.001). Regarding OS, variables with a negative impact by univariate analysis were ≥25% 17p- cells by FISH (p=0.002), presence of TP53 mutations on the other allele (p=0.021), presence of 17p- by CN-SNP (p=0.022), unmutated IGHV genes (p=0.026), positive ZAP-70 expression (p=0.043) and elevated B2M (p=0.004). Genomic complexity was predictive of a shorter OS, but only by CBA. As such, patients with a complex karyotype had a significantly shorter OS (p=0.035), but not patients with ≥3 CNAs. Multivariate analysis revealed that ≥ 25% 17p- cells by FISH (HR 3.0, 95% CI 1.4–6.6, p=0.007) and B2M (HR 2.5, 95% CI 1.2–5.4, p=0.015) were the only variables with independent prognostic value. In conclusion, the prognosis of patients with a 17p- CLL is modulated by the allelic burden by FISH and genomic complexity. CN-SNP arrays were less sensitive than FISH in the detection of 17p losses, although the presence of ≥3 CNAs was particularly predictive of TTFT in patients with de novo 17p-. Disclosures: No relevant conflicts of interest to declare.

Genomic Complexity Identifies Patients with Agressive Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 489-489
Author(s):  
Sami N. Malek ◽  
Peter Ouillette ◽  
Harry Erba ◽  
Chris Saddler ◽  
Andrzej Jakubowiak ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gold Standard ◽  
Copy Number ◽  
Univariate Analysis ◽  
Visual Complexity ◽  
Snp Array ◽  
Lymphocytic Leukemia ◽  
Genomic Complexity ◽  
Complexity Score ◽  
Trisomy 12

Abstract Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. CLL has a varied clinical course. Risk assessment and patient counseling relies on clinical parameters and validated biomarkers. Genetic biomarkers, as exemplified in the CLL FISH panel, allow for CLL patient risk stratification. Nonetheless, a subset of patients with apparently favorable lesions (del13q14 or normal FISH results) progresses rapidly and a fraction of patients with unfavorable findings (del17p or del11q) progress at less than predicted rate. Method: We studied 117 previously untreated CLL patients enrolled into a prospective study at the University of Michigan. We obtained unbiased, high-density, genome-wide measurements of sub-chromosomal copy number changes in highly purified DNA from sorted CD19+ cells and buccal cells using the Affymetrix 50K SNP-array platform. A genomic complexity score was derived and correlated with the validated surrogate endpoint time to first therapy (TTFT), a measure of disease aggressiveness. Genomic complexity was measured using two complementary methods: i) visual inspection of dChipSNP-generated heatmap displays for copy-number estimates for all patients and for all chromosomes. Two of the authors independently reviewed dChipSNP-based copy number displays and visually scored lesions that were i) at least 8 consecutive SNP positions in length and ii) either all blue (indicating less than 2N copy estimates=losses) or all red (indicating greater than 2N copy estimates=gains). Sensitivities and specificities for the visual lesion calling method were calculated against the clinical FISH data for del17p, del13q14, trisomy 12 and del11q as the gold standard. Sensitivities and specificities for (SNM/PDO) were [(94%/93%) and (93%/91%)] for del13q14, [(88%/88%) and (98%/98%)] for trisomy 12, [(100%/100%) and (99%/99%)] for del17p, and [(100%/100%) and (99%/100%)] for del11q, and ii) algorithmic detection of gains and losses using search methods optimized for detection using FISH-based del13q14 lesions as the gold standard. We devised a sliding window algorithm that scores a lesion as “copy loss” when a SNP window of 8 consecutive SNPs has at least 6 SNPs with a copy number estimate of 1.32 or less (the 8/6/1.32 rule). For validation, an approximately 5 Mb-long physical window was selected, overlapping with all described del(13q14) lesions. Defining an algorithmic del(13q14) call as any patient for whom the 8/6/1.32 rule identified at least one lesion within the 5Mb window, we achieved 81% sensitivity and 96% specificity for detecting or excluding 13q14 lesions as measured against the clinical FISH panel. Results: Within the group of 117 patients, 22(19%), 15(13%), 12(10%) and 10(9%) had visual complexity scores of equal to or greater than 2.5, 3, 3.5 or 4, respectively: a previously unanticipated degree of genomic complexity in CLL.In univariate analysis, CLL patients with four or more sub-chromosomal genomic lesions had a median TTFT of 15.8 months, whereas the median TTFT for all other patients was not reached in our study (two-sided p<10−4). In bivariate analysis, presence of genomic complexity defined a high-risk group of patients within the IgVH unmutated subgroup. Patients with unmutated IgVH/high complexity score had a TTFT of 16.5 months versus 95.6 months for unmutated IgVH/low complexity patients (p=0.02). Finally, high genomic complexity resulted in strong trends towards shorter TTFT for patients within other established risk groups.

scholarly journals Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness

Blood ◽  
2014 ◽  
Vol 123 (15) ◽  
pp. 2378-2388 ◽  
Author(s):  
Monica Messina ◽  
Ilaria Del Giudice ◽  
Hossein Khiabanian ◽  
Davide Rossi ◽  
Sabina Chiaretti ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Copy Number ◽  
Lymphocytic Leukemia ◽  
Copy Number Aberrations ◽  
Key Points

Key Points The coding genome of fludarabine-refractory CLL patients is characterized by 16 mutations/case and 4 copy number aberrations per case on average. Fludarabine-refractory CLL cases are enriched in FAT1 mutations occurring in 10% of patients, suggesting a role in the refractoriness event.

Microarray-based cytogenetic profiling reveals recurrent and subtype-associated genomic copy number aberrations in feline sarcomas

2009 ◽  
Vol 17 (8) ◽  
pp. 987-1000 ◽  
Author(s):  
Rachael Thomas ◽  
Victor E. Valli ◽  
Peter Ellis ◽  
Jerold Bell ◽  
Elinor K. Karlsson ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Aberrations ◽  
Genomic Copy Number ◽  
Genomic Copy
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