High Density SNP Array Analysis of Acute Promyelocytic Leukemia (APL) Detects New Common Genomic Copy Number Alterations as Possible Cooperating Lesions

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2721-2721
Author(s):  
Daniel Nowak ◽  
Marion Klaumuenzer ◽  
Benjamin Hanfstein ◽  
Maximilian Mossner ◽  
Florian Nolte ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Promyelocytic Leukemia ◽  
Copy Number ◽  
Genomic Dna ◽  
Snp Array ◽  
Promyelocytic Leukemia ◽  
High Density ◽  
Copy Number Alterations ◽  
Array Analysis ◽  
Snp Array Analysis

Abstract Abstract 2721 Introduction: Acute Promyelocytic Leukemia (APL) is characterized by the typical chromosomal translocation t(15;17)(q22;q21) leading to the fusion product PML-RARA, which blocks granulocytic differentiation in the promyelocyte stage. Several experimental in vitro and in vivo studies have demonstrated that PML-RARA is necessary but not sufficient for the generation of APL. This circumstance has motivated the search for additional leukemogenic and cooperating molecular lesions. Patients and Methods: We have analyzed 101 APL patient bone marrow samples with high density Genome-Wide Human SNP 6.0 arrays, which interrogate >900.000 SNPs and >900.000 non-polymorphic copy number markers throughout the genome (Affymetrix, Santa Clara, CA, USA) in search for copy number alterations (CNAs) potentially relevant in the pathogenesis of APL. Genomic DNA from samples at initial diagnosis of 94 patients was analyzed. Furthermore, DNA from 11 samples at relapse was available, whereby 4 of these relapse samples also had paired DNA from initial diagnosis. Data analysis was carried out with the CNAG 3.3 software using anonymous references. For exclusion of copy number polymorphisms, all detected CNAs were compared with the databases of known copy number polymorphisms in the UCSC genome browser. For data validation, putatively acquired CNAs and regions of copy number neutral loss of heterozygosity (CNLOH) were confirmed by hybridization of DNA from paired normal samples when the patients were in remission, by quantitative real time PCR of genomic DNA and by direct sequencing of informative SNPs. Results: The high density SNP array analysis detected a total of 120 heterozygous deletions, 97 duplications or amplifications and 7 regions of telomeric CNLOH leading to an average of 2.3 CNAs per sample (range 0–30). The most common numerical and large structural aberrations were found on chromosome (chr.) 8 with either trisomy 8 (n=11) or duplication of regions on chr. 8q (n=10) followed by heterozygous deletions of chr. 7q (n=5) and chr. 16q (n=5). Furthermore, unbalanced translocations of chr. 15 and 17 involving PML and RARalpha were detected in five cases leading to duplication of the PML-RARA fusion or deletion of genomic regions flanking either PML or RARalpha. Recurrent microlesions (<1Mbp) were found in several regions as heterozygous deletions on chr. 1q31.3 containing the micro RNAs MIR181B1 and MIR181A1 (n=5), on chr. 2q32.3 containing serine/threonine kinase 17b (STK17B) (n=5) or chr. 3p24.3 containing ankyrin repeat domain 28 (ANKRD28) (n=5). One recurrent region of telomeric CNLOH was found on chr. 19q in two samples. Of note, besides the few regions of telomeric CNLOH a large number of intrachromosomal CNLOH regions (n=265) was identified, with recurrent regions on chr. 6p21.1 (n=10) or chr. 5q23.3-5q31.1 (n=6) containing genes relevant in hematopoiesis such as IL3, CSF2 or DNA damage repair such as RAD50. Although these CNLOH regions were not somatically acquired they may possibly harbor genetic predispositions for disease. Conclusions: We describe a detailed high density SNP array genomic profiling of bone marrow DNA from patients with APL, which has led to the identification of several new cryptic recurrent genomic lesions. These genomic alterations point to candidate genes, which could be cooperating factors in addition to PML-RARA. Therefore, our data helps to provide a better understanding of the molecular mechanisms underlying the development of APL. Disclosures: Kohlmann: MLL Munich Leukemia Laboratory: Employment. Lengfelder:Cephalon: Research Funding.

High Density SNP Array Analysis of Tyrosine Kinase Inhibitor (TKI) Resistant Chronic Myeloid Leukemia (CML) Shows Secondary Genomic Alterations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3182-3182
Author(s):  
Daniel Nowak ◽  
Norihiko Kawamata ◽  
Tadayuki Akagi ◽  
Ryoko Okamoto ◽  
Nils Thoennissen ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Snp Array ◽  
High Density ◽  
Array Analysis ◽  
Snp Arrays ◽  
Tki Resistance ◽  
Snp Array Analysis

Abstract Despite the success story of tyrosine kinase inhibitors (TKIs) for the treatment of Chronic Myeloid Leukemia (CML), patients can develop resistances against the drugs. The main known causes for resistance are mutations or over-expression of the BCR/ABL fusion protein, reduced bioavailability of the drugs and activation of compensatory molecular pathways. It is hypothesized that during disease progression, genomic instability of CML cells increases, which may lead to new genomic lesions harboring additional mechanisms of resistance. In this context, we studied genomic DNA profiles of 32 Imatinib resistant CML patients with high density 250K SNP arrays (Affymetrix). Molecular allelokaryotyping for allele specific copy number and loss of heterozygosity analysis was performed with the CNAG software. Single DNA samples from 27 patients were extracted after they had acquired resistance to Imatinib or alternative TKIs such as Nilotinib or Dasatinib. DNA from 12 patients could be analyzed in sequential samples from the initial diagnosis timepoint and a second timepoint upon the emergence of TKI resistance. All patients were positive for BCR/ABL by PCR and FISH. 10 relapse patient samples had known BCR/ABL mutations of which two were T315I mutations. High density allelokaryotyping confirmed pre-existent data on unbalanced translocations, amplifications and deletions from routine cytogenetics: 5 samples displayed a genomic duplication of the BCR/ABL fusion gene, 4 samples had trisomy 8, 1 sample showed deletion of chromosome 17p, 1 sample had heterozygous deletion of chromosome 9. Apart from this, SNP array analysis revealed numerous new submicroscopic genomic lesions. After exclusion of genomic copy number polymorphisms (CNPs) by comparison to recorded CNPs in the UCSC Genome Browser (http://genome.ucsc.edu/) the following results were obtained: Two patients displayed common heterozygous microdeletions of the reciprocal ABL/BCR fusion product. Furthermore, single samples displayed heterozygous micro-deletions on chromosomes 1, 2, 10, 12, 15, 17, and 22 or microduplications on chromosomes 2,3,6, 8, 9, 11, 12, 14, 15, 22. The affected regions contained potentially interesting genes in respect to resistance to therapy such as tumor suppressor candidate MBP-1, apoptosis related protein RERE, metastasis associated gene MTA3, nuclear body associated gene SP100, alpha-T-catenin (CTNNA3), Cbl-interacting protein Sts-1 and the DNA repair associated gene RAD51. As a new genomic alteration in CML, we detected acquired uniparental disomy (UPD) in 5 samples with a common site of UPD on chromosome 19q in 2 patients. In conclusion, in 14 out of 39 TKI resistant cases, high density SNP arrays enabled us to identify submicroscopic copy number lesions and regions of UPD containing promising candidate genes, which merit further research as sites conferring TKI resistance.

Large Regions of Uniparental Disomy (UPD) Establish Clonal Hematopoietic Stem Cell Selection in a Subset of Myelodysplastic Syndrome (MDS) Patients with Normal Bone Marrow Cell Karyotypes.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 120-120 ◽  
Author(s):  
Stefan Heinrichs ◽  
Rima V. Kulkarni ◽  
Carlos E. Bueso-Ramos ◽  
Mignon Loh ◽  
Ross Levine ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cytogenetic Analysis ◽  
Copy Number ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Normal Bone Marrow ◽  
Array Analysis ◽  
Normal Bone ◽  
Snp Array Analysis

Abstract Myelodysplastic syndromes (MDS) comprise a large group of hematological diseases sharing clinical features, but the diverse mechanisms underlying their molecular pathogenesis remain largely undefined. In this study, we used high-density 250K SNP arrays to analyze matched constitutional (buccal) and whole bone marrow DNAs from 36 patients with MDS. In 14 cases, we also selected CD34+ stem and progenitor cells for comparison. 23 of the cases were cytogenetically normal. Whereas regions of genomic amplification were rare, we found distinct regions of heterozygous deletion in 9 patients, most frequently targeting chromosomes 5q, 7q, 17p and 20q. In one patient with a large heterozygous 5q deletion, a smaller region in 5q34 was homozygously lost. Based on genotyping we could identify regions of uniparental disomy (UPD) in 4 patients, three of whom had normal bone marrow karyotypes. Two of the regions of UPD targeted chromosome 7q, suggesting that the frequency of 7q deletion is underestimated by conventional cytogenetics, and that a mutation has occurred in these cases within the reduplicated region involved in UPD. Comparison with constitutional DNA was critical for accurate SNP analysis in MDS, allowing us to focus on acquired clonal abnormalities and control for changes due to inherited copy number variation or unusual regions of germline homozygosity. For example, one case had several large blocks of germline homozygosity distributed over various chromosomes, and by comparison with the buccal DNA we were able to discern that these regions did not result from clonal somatic abnormalities associated with MDS. The analysis of CD34+ cellular DNA in 14 cases revealed that all aberrations identified in the stem and progenitor fraction were also identified in whole bone marrow DNA. This finding emphasizes the dominance and stem cell involvement of the abnormal clone in MDS, which makes purification of CD34 cells unnecessary for SNP array analysis in this disease. Most, but not all, clonal deletions evident by cytogenetic analysis were detected as copy number alterations by SNP array, possibly indicating that such abnormalities occurred in subpopulations of the cytogenetically analyzed MDS cells. Thus, SNP array and cytogenetic analysis are complementary methods for the identification of abnormal clones in MDS patients, each detecting overlapping but distinct subsets of patients. Our data indicate that SNP array analysis should be performed in all patients with MDS and normal bone marrow cytogenetics, in order to help discriminate patients with UPD indicating cell autonomous clonal stem cell malignancy from those who might have extrinsically mediated bone marrow failure syndromes.

Genomic DNA Copy Number Alterations Present in AML Bone Marrow Samples with Normal Cytogenetics.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 142-142 ◽  
Author(s):  
Matthew J. Walter ◽  
Rhonda E. Ries ◽  
Jon Armstrong ◽  
Brian O’Gara ◽  
James W. Vardiman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Copy Number ◽  
Genomic Dna ◽  
Array Cgh ◽  
Comparative Genomic ◽  
Copy Number Alterations ◽  
Dna Copy Number ◽  
Prognostic Information ◽  
Normal Cytogenetics ◽  
Copy Number Changes

Abstract Cytogenetics and comparative genomic hybridization (CGH) have been used to identify large genomic amplifications and deletions in all subtypes of acute myeloid leukemia (AML). Up to 15–20% of AML patients have a normal karyotype at diagnosis. While cytogenetic abnormalities confer important prognostic information for patients with AML, there remain differences in the therapeutic response and outcome among patients with the same cytogenetic profile, implying that other, more subtle, genetic abnormalities may exist. We hypothesized that a subset of AML patients with normal cytogenetics may contain genomic DNA copy number changes that are too small to be detected using standard cytogenetic techniques. To address this possibility, we used high-resolution bacterial artificial chromosome (BAC) array CGH technology to examine 31 AML patients with normal cytogenetics. The BAC arrays contain 2,464 BAC clones spotted in triplicate on glass slides, and provide a 1 Mb resolution of the entire human genome. Technical generation of the arrays, hybridization parameters, and analysis were similar to that reported for murine BAC array CGH (Nat Genet. 2001 Dec;29(4):459–64). The 31 AML samples included 4 M0, 8 M1, 10 M2, and 9 M4 patients. Array CGH experiments were performed using 500 nanograms of Cyanine 5 labeled genomic DNA from unmanipulated AML bone marrow, mixed with an equal amount of control DNA (a pool of DNA from 4 cancer-free individuals) labeled with Cyanine 3. Using the human 1 Mb BAC arrays, we identified amplifications and deletions from multiple samples that were confirmed with G-banding cytogenetics [del(7)(q31), del(7)(p11.2), +8, del(11)(q13q23), +21, add(21)(q22), −X, −Y, +Y]. In addition, BAC arrays robustly detected copy number alterations that were identified in as few as 4/21 metaphases. We identified 5/31 (16%) patients with normal cytogenetics that contained altered genomic DNA copy numbers using BAC array CGH. Copy number changes were confirmed for several of these genomic loci using a dye-swap experiment, where the AML DNA was labeled with Cyanine 3, and the control DNA with Cyanine 5. Two of the 5 patients with abnormalities detected using array CGH would be reclassified from “intermediate” to “unfavorable” cytogenetics [del(7)(q31.31q34), add(11)(q23.3qter), and 17(p12pter)]. These results suggest that a subset of AML patients with normal cytogenetics contain genomic copy number alterations that may effect treatment and outcome. Patient # FAB subtype Genomic location Gain or loss Size (Megabase) Dye-Swap confirmed 1 M0 7(q31.31q34) loss 2.0 Not done 1 11(q23.3qter) gain 16.5 Not done 2 M1 11(p14) loss 7.4 Yes 3 M1 11(q13.2q14.1) gain 15.8 Yes 3 19(p) gain 64.0 Yes 4 M2 17(p12pter) gain 8.6 Not Done 5 M2 19(p13.1pter) loss 14.8 Yes 5 12(q13) loss 5.0 Yes

SNP Array Analysis Reveals Copy Number Alterations and Uniparental Disomy in Mantle Cell Lymphomas at High Resolution.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1585-1585
Author(s):  
Elena M. Hartmann ◽  
Itziar Salaverria ◽  
Silvia Bea ◽  
Andreas Zettl ◽  
Pedro Jares ◽  
...  
Keyword(s):  
High Resolution ◽  
Cell Lines ◽  
Copy Number ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Genetic Alterations ◽  
Array Analysis ◽  
Snp Array Analysis ◽  
Copy Number Changes ◽  
500K Array

Abstract Mantle Cell Lymphoma (MCL) is an aggressive B-Cell Non Hodgkin Lymphoma which is genetically characterized by the translocation t(11;14). This translocation leads to juxtaposition of the Cyclin D1 gene and the IgH locus, resulting in constitutive overexpression of Cyclin D1 and consecutive cell cycle dysregulation. Apart from this typical structural genetic alteration, several studies using conventional or array-based comparative genomic hybridization (CGH) reported a high number of secondary numerical genetic alterations contributing to MCL lymphomagenesis and influencing the clinical behavior. Increasingly, there is evidence that loss of heterozygosity (LOH) without copy number changes (e.g. caused by mitotic recombination between the chromosomal homologues, also referred to as acquired (partial) uniparental disomy (a(p)UPD), is an important alternative mechanism for tumor suppressor gene inactivation. However, this phenomenon is undetectable by CGH techniques. Single Nucleotide Polymorphism (SNP) based arrays allow - in addition to high resolution copy number (CN) analyses and SNP genotyping - in the same experiment the analysis of loss of heterozygosity (LOH) events and hereby enable the detection of copy neutral LOH. We analyzed the 3 t(11;14)-positive MCL cell lines Granta 519, HBL-2 and JVM-2 and 5 primary tumor specimens from untreated MCL patients with both the Affymetrix GeneChip®Human Mapping 100K and 500K array sets. In the 3 cell lines, we found an excellent agreement between the copy number changes obtained by SNP array analysis and previously published array CGH results. Extending published results (Nielaender et al., Leukemia 2006), we found regions of pUPD in all 3 MCL cell lines, which often affected regions reported as commonly deleted in MCL. Intriguingly, HBL-2 that is characterized by relatively few chromosomal losses, carries an increased number of large regions showing copy neutral LOH. Furthermore, we compared the results obtained by the 100K and 500K mapping array sets from 5 primary MCL tumor specimens with previously published conventional CGH data. All cases showed genetic alterations in both conventional CGH and SNP array analysis. The total number of copy number alterations detected by conventional CGH was 35, including 23 losses, 10 gains and 2 amplifications. The total number of CN alterations detected by the mapping 100K and 500K array sets was 81 (50 losses, 26 gains and 5 amplifications) and 82 (50 losses, 27 gains and 5 amplifications), respectively. We found an excellent agreement in the large CN alterations detected by conventional CGH and both SNP array platforms. Furthermore, we identified &gt;40 mostly small CN alterations that have not been detected by conventional CGH (median size &lt;5MB for losses and &lt;3Mb for gains). The CN alterations detected by the 100k and the 500K array sets were highly identical. Importantly, we discovered regions of partial UPD in 4 of the 5 MCL cases (size range from around 2Mb up to a single region &gt;40Mb). In conclusion, the results demonstrate the capability of SNP array analysis for identifying CN alterations and partial UPD at high resolution in MCL cell lines as well as in primary tumor samples.

Genome-Wide DNA Copy Number Analysis by SNP Arrays of B-Cell Chronic Lymphocytic Leukemia: Correlation with Known Biological and Molecular Prognostic Markers.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1061-1061
Author(s):  
Laura Mosca ◽  
Sonia Fabris ◽  
Giovanna Cutrona ◽  
Luca Agnelli ◽  
Serena Matis ◽  
...  
Keyword(s):  
High Resolution ◽  
Copy Number ◽  
Prognostic Markers ◽  
Snp Array ◽  
Lymphocytic Leukemia ◽  
Array Analysis ◽  
Genome Wide ◽  
Trisomy 12 ◽  
Snp Array Analysis ◽  
Cell Chronic Lymphocytic Leukemia

Abstract B-cell chronic lymphocytic leukemia (B-CLL) is a genetically heterogeneous disease with a variable clinical course. Chromosomal changes have been identified by FISH in approximately 80% of patients, and the presence of specific lesions, such as trisomy 12 and 13q14, 11q23, 17p13.1 and 6q23 deletions represent prognostic markers for disease progression and survival. In order to characterize further the complexity of B-CLL genomic lesions, we performed high density, single nucleotide polymorphism (SNP) array analysis in highly purified neoplastic cells (&gt;92%) from a panel of 100 untreated, newly diagnosed patients (57 males and 43 females; age, median 63 years, range 30–87) in Binet stage A. All patients were investigated by FISH for the presence of trisomy 12 (21 cases); 13q14 deletion (44 cases, 34 as the sole abnormality); 11q22.3, 17p13.1 and 6q23 (15, 7 and 2 patients, respectively). In addition, ZAP-70 and CD38 expression resulted positive in 42 and 46 patients, whereas IgVH genes were mutated in 45 patients. Genome-wide DNA profiling data were generated on GeneChip® Human Mapping 250K NspI arrays (Affymetrix); copy number alterations (CNA) were calculated using the DNA copy Bioconductor package, which looks for optimal breakpoints using circular binary segmentation (CBS) (Olshen et al, 2004). A total of 782 CNAs (ranging from 1 to 31 per sample, mean and median values 7.82 and 7, respectively) were detected; DNA losses (365/782=46.67% loss; 194/782=24.81% biallelic deletion) were found to be more frequent than gains (148/782=18.93% gain; 75/782=9.59% amplification). The most recurrent alterations detected by FISH were all confirmed by SNP array analysis, strengthening further the good reliability of such high-resolution technology. We identified 12 minimally altered regions (MARs) larger than 100 kb with a frequency higher than 5%. Among well known alterations, the largest was represented by chromosome 12 trisomy, followed by 6q, 17p and 11q23 deletions (32.87, 19.09 and 10.43 Mb, respectively) and 13q14 deletion (635 kb). Gain of 2p25.3 involves a common region of 4.39 Mb region in 7 patients, although it was extended to the whole short arm of chromosome 2 in 3 cases. Among those alterations previously described in B-CLL, we found losses at 14q32.33 (12 pts) and 22q11.2 (5 pts) involving the IGH and IGLλ loci, respectively. With regard to novel regions, we identified losses at 4q35.2 (5 pts) and 11q25 (6 pts). In addition we found a high frequency of losses/gains at 14q11.2 (42 pts) and 15q11.2 (33 pts), two genomic regions reported to be affected by DNA copy number variations in normal individuals. As regards correlations between CNAs and biological markers, we found that the number of CNAs is significantly higher in cases with unmutated IgVH (9.4; range 2–31) as compared with mutated IgVH (6; range 1–13) (p=0.002), while neither CD38 nor ZAP-70 expression showed significant correlation. In addition, a significant higher number of either CNAs (p=0.001), total MARs (p&lt;0.0001) or even only novel MARs (p=0.009) was significantly associated with cases with 17p deletion or multiple cytogenetic aberrations as evaluated by FISH analysis. Our data indicate that genetic abnormalities involving chromosomal gains and losses are very common in early-stage B-CLL and further support the application of high resolution SNP array platforms in the characterization of genetic changes in the disease. In addition, we detected novel altered chromosomal regions that warrant further investigations to better define their pathogenetic and prognostic role in B-CLL.

SSBP2-CSF1R Is a Recurrent Fusion in B-Other Acute Lymphoblastic Leukaemia with Variable Clinical Outcome

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3773-3773 ◽  
Author(s):  
Claire Schwab ◽  
Rebecca Andrews ◽  
Lucy Chilton ◽  
Alannah Elliott ◽  
Stacey Richardson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Snp Array ◽  
Fish Analysis ◽  
Cell Transplant ◽  
Chromosome 5 ◽  
Array Analysis ◽  
Snp Array Analysis

Abstract BCR-ABL1-like acute lymphoblastic leukaemia (ALL) is a subgroup of B cell precursor (BCP) ALL, which has a similar gene expression profile to BCR-ABL1 positive ALL and shares the same high risk of relapse. BCR-ABL1-like ALL is genetically heterogeneous and no single abnormality defines them. However a number of novel fusion genes have been reported in this subgroup, which involve the kinase genes: PDGFRB, CSF1R, ABL1, ABL2 and JAK2. Studies have shown that patients with these fusions may also respond to tyrosine kinase inhibitors (TKI), such as imatinib. Here we present a subset of patients with the SSBP2-CSF1R fusion, including a patient treated with imatinib after relapse. Five patients with BCP-ALL were identified with cytogenetically visible abnormalities of chromosome 5, which resulted in fusion of the SSBP2 at 5q14 to CSF1R at 5q33. Three patients showed balanced translocations, t(5;5)(q14;q33) and 2 showed duplication of the long arm of chromosome 5, dup(5)(q14q33). FISH analysis using in-house dual colour break-apart probes confirmed rearrangement of the CSF1R and SSBP2 genes in 4 patients. In the two cases showing dup(5)(q14q32) the duplication was confirmed by single nucleotide polymorphism (SNP) array analysis with the breakpoints occurring within SSBP2 and CSF1R. Paired end sequencing in 3 cases confirmed that the breakpoints within SSBP2 and CSF1R with the predicted transcriptional consequence being an in-frame fusion of SSBP2 exon 5 or 6 to CSF1Rexon 12. Genome wide SNP array analysis was performed in 4 cases, which revealed few copy number abnormalities (CNA) at diagnosis, with less than 5 CNA per patient. The only recurrent CNA was loss of IKZF1, seen in 2 patients; one had an intragenic deletion of exons 4-7 and the other a large deletion of approximately 22.5 Mb, spanning 7p11 to 7p14.2 and including biallelic loss of IKZF1exons 2-3. The clinical and demographic data for the five patients are shown in Table 1. Complete remission (CR) was achieved in all cases. Two patients, who were <10 years at diagnosis and received standard chemotherapy, have continued in CR1 for >10 years. The oldest patient was a 40 year old female who died due to graft versus host disease following a bone marrow transplant. Patients 4 and 5 were treated as high risk due to age, high WCC (>50 x109/L) and minimal residual disease (MRD) risk. Despite receiving intensive therapy, both patients suffered relapses. Patient 4, who relapsed while receiving consolidation therapy, failed to achieve CR2 and subsequently died. Patient 5 suffered an isolated bone marrow relapse one month after the end of treatment. She was treated according to the ALLR3 trial high risk arm and achieved CR2 and MRD negativity by day 35. The detection of the SSBP2-CSF1R fusion prompted the addition of imatinib (400 mg/d) to her regimen with the intention of maintaining remission until unrelated donor stem cell transplant. Unfortunately the patient died 11 weeks after relapse from infection (E. coli septicaemia). Although these cases were identified by cytogenetics, unbiased screening of a single childhood trial, UKALL2003 was carried out. Among 276 BCP-ALL patients without any of the established cytogenetic changes, a single case (Patient 4) with the SSBP2-CSF1Rfusion was identified. This equates to less than 0.1% of childhood BCP-ALL. The incidence and outcome in adult BCP-ALL remains to be determined. This study highlights the rarity and variable outcome for paediatric patients with SSBP2-CSF1R fusions. Two young children treated as low risk achieved long-term event free survival, however 2 older children classified as high risk suffered early relapses. It is possible that children with ALL who are SSBP2-CSF1Rpositive may benefit from the incorporation of TKI into their treatment regime in the early stages of their disease. Given the rarity of this abnormality, it may not be necessary to screen all children, however those with refractory or high risk ALL should be investigated for lesions potentially responsive to TKI. Table 1 Patient no. Age Sex Trial WCC(x109/L) Karyotype Follow up 1 2 M ALL97 50.3 46,XY,t(5;5)(q14q33) CR1 >10yrs 2 4 F ALL97 18.2 47,XX,t(5;5)(q14;q33),+21 CR1 >10yrs 3 40 F UKALLXII 12.1 Failed. arr [hg19] 5q14q33(80721553-149443298)x3 Remission death 4 10 M UKALL2003 301.8 46,XY,t(5;5)(q14;q33)/46,XY,idem,t(3;20)(p21;q13) Relapsed and died 5 11 F Non-trial 8 46,XX,dup(5)(q14q33)† Relapsed and died in CR2 † karyotype at relapse Disclosures No relevant conflicts of interest to declare.

Use of high-density SNP-array analysis to identify novel chromosomal abnormalities that predict survival in multiple myeloma

2008 ◽  
Vol 26 (15_suppl) ◽  
pp. 8522-8522 ◽  
Author(s):  
H. Avet-Loiseau ◽  
N. Munshi ◽  
C. LI ◽  
F. Magrangeas ◽  
W. Gouraud ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chromosomal Abnormalities ◽  
Snp Array ◽  
High Density ◽  
Array Analysis ◽  
Snp Array Analysis
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