Use of Single Nucleotide Polymorphism–Based Mapping Arrays to Detect Copy Number Changes and Loss of Heterozygosity in Multiple Myeloma

2006 ◽  
Vol 7 (3) ◽  
pp. 186-192 ◽  
Author(s):  
Brian A. Walker ◽  
Gareth J. Morgan
Keyword(s):  
Multiple Myeloma ◽  
Single Nucleotide Polymorphism ◽  
Loss Of Heterozygosity ◽  
Copy Number ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Copy Number Changes ◽  
Mapping Arrays

Genome-Wide Profiling of DNA Copy Number Abnormalities and Loss-Of-Heterozygosity in Pediatric Acute Myeloid Leukemia Using High-Resolution Single Nucleotide Polymorphism Microarrays.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 106-106
Author(s):  
Ina Radtke ◽  
Charles G. Mullighan ◽  
Salil Goorha ◽  
Jing Ma ◽  
Stanley B. Pounds ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Loss Of Heterozygosity ◽  
Copy Number ◽  
Specific Gene ◽  
Nucleotide Polymorphism ◽  
Dna Copy Number ◽  
Single Nucleotide ◽  
Snp Arrays ◽  
Pediatric Aml ◽  
Copy Number Changes

Abstract To identify a comprehensive registry of oncogenic lesions in pediatric acute myeloblastic leukemia (AML), we used Affymetrix single nucleotide polymorphism (SNP) arrays to examine changes in DNA copy number and loss-of-heterozygosity (LOH) in leukemic blasts from 112 cases of pediatric AML and corresponding remission samples from 63 of these cases. The analyzed cases included t(8;21)[AML1-ETO] (n=20), inv(16)[CBFβ-MYH11](n=16), t(15;17)[PML-RARα] (n=7), MLL rearranged (n=17), FAB M7 (n=9) and normal cytogenetics or miscellaneous cytogenetic abnormalities (n=43). Four SNP arrays (50K Hind and Xba, 250K Sty and Nsp) were used to interrogate over 615,000 markers at a mean inter-marker distance of 4.8 kb. Combined data were analyzed using dChipSNP and a modified array normalization algorithm using only those SNPs from regions known to be diploid by routine karyotyping. These analyses not only detected known whole or partial chromosomal losses or gains, but also detected numerous copy number abnormalities that were not evident by conventional cytogenetics. Somatic DNA copy number abnormalities were identified in 102 (91.1%) cases. The mean number of lesions per patient was 3.2 (range 1–12), with a mean of 2.13 deletions/whole chromosome losses and 1.02 amplifications/whole chromosome gains per patient. Deletions were detected in the leukemic blasts from over 90% of patients, whereas amplifications were only seen in the leukemic blasts from 54% of patients. The vast majority of deletions were focal (<20 Mb) with less than 20% of cases containing larger deletions or losses of whole chromosomes or chromosomal arms. No differences in the frequency of deletions were observed among the different genetic sybtypes of AML. Lesions identified in 2 or more cases included deletions of CDKN2A/B (9p21.3, n=4) and FOXE1 (9p22, n=3), and amplifications of ETS1 (11q24.3, n=3) and MYST4 (10q22.2, n=2). For each of the listed genes, at least one case was identified harboring a focal deletion or amplification confined to the specific gene, thus definitively identifying the gene as the target of the alteration. In addition to these recurrent lesions, copy number changes were identified in regions containing 5 or fewer genes in single cases, including deletions involving the tumor suppressor candidate TUSC3 (8p22), alpha 3 catenin (10q21.3), and amplifications involving FGFR activating protein 1 and RAS homolog G (11p15.4). Importantly, within our cohort of de novo AMLs no focal sub-microscopic lesions involving 5q or 7q were identified. Similarly, copy-neutral LOH (uniparental disomy) that was not adjacent to an identified region of deletion or amplification was uncommon. Taken together, these data demonstrate a surprisingly low frequency of copy number changes in pediatric AML with focal deletions measured at an average resolution of 5-10 KB across the genome predominating over focal amplifications. Moreover, the identified lesions appear to target a rather large number of different genes. Correlating the identified copy number changes with mutations in other genes known to be involved in leukemogenesis including, NRAS, KRAS, FLT3, NPM1, CEBPA, BRAF, PTPN11, AML1 and KIT, should provide valuable insights in the molecular pathology of AML.

Whole Genome Association Study in Leukemia: Frequent Loss of Heterozygosity (LOH) and Single Nucleotide Polymorphism (SNP) in Acute Myeloid Leukemia with a Normal Karyotype.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2838-2838
Author(s):  
Young Y. Lee ◽  
Joowon Park ◽  
Sung-Soo Yoon ◽  
Kwang-Sung Ahn ◽  
Jung H. Choi ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Whole Genome ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Copy Number Changes ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous disease with various chromosomal aberrations. The karyotype at diagnosis is generally recognized as the single most valuable prognostic factor. However, using conventional cytogenetic techniques, karyotype abnormalities are detected in only half of all AML cases and the other half are commonly described as normal-karyotype AML. Patients with normal-karyotype AML are classified as an intermediate risk group with a 5-year overall survival of between 35% and 45%, but clinical outcome may vary greatly. Also, classical cytogenetic methods are limited in resolution and dependent on highly skilled labor. Therefore, the appropriate choice of additional treatment in patients who attained first remission (chemotherapy versus autologous transplantation versus allogeneic transplantation) is unclear for these patients. Thus, additional markers with prognostic significance are needed to identify clinically relevant subgroups among AML patients with a normal karyotype. Recently, human genome-wide studies gain popularity to identify the genetic basis of complex disorders such as AML. Altered transcript levels in AML genomes are often related to copy number changes, and genome-wide detection of allelic imbalance in AML cells by polymorphic genetic markers has become an important technique to identify genetic events involved in the progression of AML. By using high density single-nucleotide polymorphism (SNP) microarrays designed to genotype more than 300K SNPs in the human genome DNA, the resolution of the whole genome scanning technique has increased considerably and allowed accurate and reproducible determination of copy number changes in whole genome of AML. It became possible to distinguish between LOH regions with underlying homozygous deletions and those with copy-neutral events. In the present study, we performed genetic changes in untreated AML with normal cytogenetics with infinium 300K SNP chip. SNP-based mapping array data and fluorescence in situ hybridization (FISH) copy number data correlated well. The most frequently identified alterations are located at 3p, 6q, 8p, 13q, 21q and 22p. LOH is found in these large regions and also in smaller regions throughout the genome with a median size of 1 Mb. Alterations was correlated with response to chemotherapy. Twenty six candidate genes showed significant evidence of linkage in the presence of disequilibrium, and ten of these were expressed in AML patients who failed to attain remission. Three other genes showing statistical evidence were not expressed. Many of the genes reported here have not been previously reported in relation to progression of AML. We show that this panel of markers adds important prognostic information for this largest subgroup in AML.

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