scholarly journals Single Nucleotide Polymorphism Array-Based Signature of Genetic Ploidy Groups in Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1473-1473
Author(s):  
Thomas Creasey ◽  
Amir Enshaei ◽  
Kathryn Watts ◽  
Gavin Cuthbert ◽  
Claire Schwab ◽  
...  
Keyword(s):  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Snp Array ◽  
Cell Populations ◽  
Nucleotide Polymorphism ◽  
Log2 Ratio ◽  
Mixed Cell ◽  
Single Nucleotide ◽  
Snp Arrays ◽  
Good Risk

Acute lymphoblastic leukemia (ALL) is characterised by a number of recurrent chromosomal abnormalities which inform prognosis. Low hypodiploidy (HoTr) and high hyperdiploidy (HeH) are genetic subgroups associated with large non-random ploidy shifts, specifically 30-39 chromosomes and 51-65 chromosomes respectively. HoTr ALL often presents with a near triploid karyotype of 60-78 chromosomes through chromosomal endoreduplication without cytokinesis. This presents a diagnostic challenge in distinguishing this poor risk entity from good risk HeH ALL. To date, classification of such challenging cases has been based on the modal chromosome number, the pattern of specific gains, and identification of loss of heterozygosity (LOH) using single nucleotide polymorphism (SNP) arrays where possible. However, loss of cellular context and mixed cell populations (normal diploid, low hypodiploid and near-triploid) when analysing SNP arrays can pose additional analytical difficulty. The aim of this SNP array study was to (1) determine the level of inaccurate genetic subgrouping when cytogenetics only was used to distinguish HeH from doubled up HoTr and (2) develop a diagnostic algorithm to reliably call HeH and HoTr without supporting cytogenetic analysis. SNP arrays were performed on diagnostic ALL samples of 85 patients (46 HoTr, 39 HeH) using Illumina CytoSNP 850k (n=80) or Affymetrix Cytoscan HD (n=5) arrays. Probe level data were uploaded to Nexus Copy Number 10 (BioDiscovery) and manual segments spanning the length of each chromosome were created. No further data pre-processing was carried out and log2 ratio of 0 was automatically assigned to the median log2 ratio of the sample. Chromosomal log2 ratios were normalized within each sample and a variety of machine-learning techniques used to cluster the samples independently of assigned diagnosis. Cases residing in the incorrect cluster based on initial diagnosis were examined in detail using information from cytogenetics and SNP array interpretation. SNP arrays were analysed from 46 HoTr (median age 50.5 years (range 7-87), 43% male) and 39 HeH (median age 7 years (range 1-58), 56% male) patients. Unsupervised clustering of log2 ratios showed a clear distinction between HeH and HoTr patients (figure (A)). Six cases clustered incorrectly based on cytogenetic diagnosis. After detailed interpretation of all cases, including identifying LOH affecting chromosomes 3, 7, 15, 16 and 17, 3/6 cases initially classified as HeH were highly suggestive of HoTr ALL despite having <60 chromosomes. Similarly, 1/6 cases was cytogenetically diagnosed with HoTr but had a SNP array pattern typical of HeH ALL. We identified chromosomes 1, 4, 11, 17, 19, and 21 as those contributing most to the distinction in the HoTr and HeH signatures with the log2 ratio of chromosome 1 the most highly discriminatory in this cohort. Using whole chromosome log2 ratios, HoTr and HeH ALL have distinct profiles. SNP array analysis highlighted at least 4 patients whose ploidy subgroups appeared incorrectly called by cytogenetics, which can affect risk stratification. Crucially, these data call into question the accepted modal chromosome numbers for HeH and HoTr in the near triploid phase and suggest this alone cannot be used to classify patients into these ploidy groups. All samples incorrectly classified as HeH ALL were from adults aged >40 years, suggesting this good risk subgroup is even rarer than previously thought in older adults. After re-classification, our cohort only contained 5/41 adults >40 years with HeH ALL, signifying that HoTr ALL is the commonest genetic ploidy group in older adults with ALL and must still be considered in cases with 50-60 chromosomes. Copy number analysis from SNP arrays is challenging in samples with marked ploidy shift and mixed cell populations. Importantly, a number of our samples had significant contaminating normal DNA and LOH could not be confirmed visually (figure (B)), underlying the need for additional factors to aid classification. Our analysis only takes into account log2 ratio of entire chromosomes, thus permitting a measure of the relative over and under-representation of specific chromosomes within the sample. This method accurately clusters patients even when LOH cannot be clearly visualized from B-allele frequency due to contaminating non-leukemic DNA and supports the development of a diagnostic classifier based on chromosomal log2 ratios. Disclosures Fielding: Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.

scholarly journals Clinical Utility and the Yield of Single Nucleotide Polymorphism Array in Prenatal Diagnosis of Fetal Central Nervous System Abnormalities

2021 ◽  
Vol 8 ◽  
Author(s):  
Meiying Cai ◽  
Hailong Huang ◽  
Liangpu Xu ◽  
Na Lin
Keyword(s):  
Central Nervous System ◽  
Single Nucleotide Polymorphism ◽  
Copy Number ◽  
Chromosomal Abnormalities ◽  
Karyotype Analysis ◽  
Snp Array ◽  
Copy Number Variations ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Pathogenic Cnvs

Applying single nucleotide polymorphism (SNP) array to identify the etiology of fetal central nervous system (CNS) abnormality, and exploring its association with chromosomal abnormalities, copy number variations, and obstetrical outcome. 535 fetuses with CNS abnormalities were analyzed using karyotype analysis and SNP array. Among the 535 fetuses with CNS abnormalities, chromosomal abnormalities were detected in 36 (6.7%) of the fetuses, which were consistent with karyotype analysis. Further, additional 41 fetuses with abnormal copy number variations (CNVs) were detected using SNP array (the detection rate of additional abnormal CNVs was 7.7%). The rate of chromosomal abnormalities, but not that of pathogenic CNVs in CNS abnormalities with other ultrasound abnormalities was significantly higher than that in isolated CNS abnormalities. The rates of chromosomal abnormalities and pathogenic CNVs in fetuses with spine malformation (50%), encephalocele (50%), subependymal cyst (20%), and microcephaly (16.7%) were higher than those with other isolated CNS abnormalities. The pregnancies for 36 cases with chromosomal abnormalities, 18 cases with pathogenic CNVs, and three cases with VUS CNVs were terminated. SNP array should be used in the prenatal diagnosis of fetuses with CNS abnormalities, which can enable better prenatal assessment and genetic counseling, and affect obstetrical outcomes.

Genetic Profiling of Adult Acute Lymphoblastic Leukemia Cells by Single Nucleotide Polymorphism Oligonucleotide Microarray.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2807-2807
Author(s):  
Ryoko Okamoto ◽  
Seishi Ogawa ◽  
Tadayuki Akagi ◽  
Motohiro Kato ◽  
Masashi Sanada ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Acute Lymphoblastic Leukemia ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Uniparental Disomy ◽  
Genetic Alterations ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Snp Chip ◽  
Pediatric All

Abstract Acute lymphoblastic leukemia (ALL) is a malignant disease of bone marrow cells, resulting from accumulation of genetic alterations of these cells. We analyzed 74 adult ALL samples by single-nucleotide polymorphism DNA microarray (SNP-Chip) using the new algorithm AsCNAR (allele-specific copy-number analysis using anonymous references). 71 samples (96%) showed genomic abnormalities in a mean 4.5 chromosomes including duplications, deletions and loss of heterozygosity with normal copy number [we call this uniparental disomy (UPD)]. About 25% of samples had a normal karyotype but each had genomic changes detectable by SNP-Chip. Importantly, 21 cases (28%) had UPD, and 29% of these had 9p UPD. Other genomic defects included deletions of p16INK4A in 18 cases (24%), deletions of ETV6 in 7 cases (9%), and hyperdiploidy (>50 chromosomes) in 3 cases (4%). In contrast, we also analyzed 399 pediatric ALL samples and deletions occurred in p16INK4A (28%) and ETV6 (22%) and 29% cases had hyperdiploidy. Hyperdiploidy is associated with a good prognosis and occured much more frequency in pediatric ALL (29%) than adult ALL (4%) which may in part explain the better prognosis in pediatric ALL compared to adult ALL. Also, small copy number changes were detected in adult ALL including deletion of B-cell differentiation genes: EBF (4 cases, 5%), Pax5 (5 cases, 7%) and IKZF (Ikaros) (8 cases, 11%), as well as, deletion of miR-15a and miR-16-1 (2 cases, 3%), which is often found in CLL. Amplification of Rel and BCL11A occurred in one case and amplification of Akt2 occurred in another case. Moreover, we found PAX5/ETV6 fusion in one case (1%); in comparison, 14 of 399 pediatric ALL cases (4%) had PAX5 fusion genes. In summary, we discovered hidden abnormalities including small copy number change and UPD in adult ALL and identified differences between adult and pediatric ALLs. In the future, routine SNP-Chip analysis may provide novel subclassification criteria for ALL and identify unique therapeutic targets.

High Resolution Genomic Profiling Using Single Nucleotide Polymorphism Microarrays Identifies Multiple Novel Genomic Lesions in Pediatric Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 108-108
Author(s):  
Charles G. Mullighan ◽  
Salil Goorha ◽  
Ina Radtke ◽  
James Dalton ◽  
Jing Ma ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Acute Lymphoblastic Leukemia ◽  
High Resolution ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Chromosome 9 ◽  
Copy Number Analysis ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Pediatric Acute Lymphoblastic Leukemia

Abstract To obtain a comprehensive registry of oncogenic lesions in pediatric acute lymphoblastic leukemia (ALL), we used Affymetrix single nucleotide polymorphism (SNP) arrays to examine changes in DNA copy number and loss-of heterozygosity (LOH) in leukemic blasts and matched remission samples from 250 ALLs. We studied B-progenitor ALLs with high hyperdiploidy, n=39; ETV6-RUNX1, n=47; MLL rearranged, n=11; TCF3-PBX1, n=17; BCR-ABL1, n=9; low hyperdiploidy, n=23; hypodiploidy, n=10; unclassified cases, n=42; and 50 T-lineage ALLs. Four arrays (50K Hind and Xba, 250K Sty and Nsp) were used to interrogate over 615,000 loci at a mean inter-marker distance of 4.8 kb. Data was analyzed using dChipSNP and a modified array normalization algorithm using only SNPs from regions known to be diploid by routine karyotyping. Copy number abnormalities were confirmed by FISH and genomic quantitative PCR. Complementary methylation analysis and sequencing of candidate genes was performed. 84% of B-ALLs and 96% of T-ALLs had at least one region of somatic deletion, and excluding cases with high hyperdiploidy, 68% of B-ALLs and 50% of T-ALLs had at least one region of somatic amplification. These included previously identified abnormalities including chromosomal duplications in hyperdiploid B-ALL; 1q duplication in TCF3-PBX1 ALL; and deletions of 9p21 (harboring CDKN2A/B, 70% of T-ALLs, 34.5% of B-ALL), 12p13 (ETV6; 25.5% of B-ALLs, 10% of T-ALLs), 6q16 (22 cases) and 11q (15 cases). The resolution of the arrays enabled precise mapping of the minimal regions of deletion at 9p21 to CDKN2A, and at 12p13 to ETV6. Combined LOH and copy number analysis identified several patterns of 9p21 abnormality: focal hemizygous deletion with corresponding LOH; focal homozygous and flanking hemizygous loss with corresponding LOH, indicating two focal deletional events; and focal homozygous loss with LOH of all of 9p or chromosome 9, indicating loss of the normal 9 or 9p and duplication of the chromosome or chromosomal arm containing the focal deletion. Copy-neutral LOH without any focal deletion in the affected region was uncommon. Deletions involving other genes with potential roles in leukemogenesis were identified including BTG1 (17 cases), ERG (10), FHIT (14), mir-16/-15a (19), MYB (5), NF1 (9), the glucocorticoid receptor NR3C1 (11), PTEN (4), and RB1 (20). Furthermore, deletions, translocations, amplifications, and point mutations of genes that regulate B-cell development and differentiation, including EBF, PAX5, Ikaros and Aiolos, were identified in 40% of B-ALL. For each of the listed genes, cases were identified that contained focal deletions limited to the specific gene. Overall, 73.6% B-ALL and 88% T-ALLs harbored deletions of one of the common lesions listed above, with 48% of B-ALLs and 48.5% of T-ALLs having multiple common lesions. The average number of deletions per case was 3.8 and 5.7 for B and T-lineage ALLs respectively. By contrast, when hyperdiploid cases were excluded, it was rare to find more than 2 regions of amplification in a single case, and the majority of cases contained no amplifications. These findings show the power of high-resolution copy number analysis for the identification of new genetic lesions in cancer, and demonstrate that multiple genetic abnormalities contribute to leukemogenesis in pediatric ALL.

Genome-Wide Detection of Copy Number Variation and Identification of Genes Associated with Risk of Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4047-4047
Author(s):  
Il-Kwon Lee ◽  
Nan Young Kim ◽  
Hee Nam Kim ◽  
Yeo-Kyeoung Kim ◽  
Je-Jung Lee ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Single Nucleotide Polymorphism ◽  
Chromosomal Aberrations ◽  
Copy Number ◽  
Snp Array ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Synonymous Snps ◽  
Genome Wide ◽  
Resolution Single

Abstract Abstract 4047 Background: Despite increasing efforts to characterize the role of copy number variants (CNVs) in MM, the genetic contribution to multiple myleoma (MM) has not been fully elucidated. Recent studies showed that chromosomal aberrations are detectable in MM and can be associated with susceptibility to MM. To gain insight into the incidence of the chromosomal aberrations in MM, we examined Korean MM genomes using high-resolution single-nucleotide polymorphism (SNP) array-based analysis. Patients and Methods: As part of a larger cohort study, 14 cases analyzed had been diagnosed with MM (9 male, 5 female). Median age at diagnosis was 58 years (range, 40≂f74). Of these patients, five patients had Ig Kappa type, five with IgG Lambda, two with light chain Kappa and two with light chain Lambda. 1,140,419 CNV markers were considered on these samples using Illumina HumanOmni1-Quad v1 BeadChip. Genome-wide CNV, genotyping of markers including 32119 non-synonymous SNPs, loss of heterozygosity (LOH) analyses were performed using the GenomeStudio v2010.1. Linkage disequilibrium was analyzed by Haploview 4.2. The gene set enrichment analysis was performed using GO software, Panther. Results: The average call rates were 99.9 %. The average number of CNVs per genome in this study (353.9) is much higher than that of CNVs called in the recent studies using lower-resolution SNP- or CNV arrays. The median size of CNVs was 1,902 (range 39 ≂f 2,263,901 bp). When we analyzed the number of CNVs per genome, there was no significant difference between MM patients of different subgroups. Interestingly copy number losses were 36.7 times more frequent than copy number gains. We defined CNV regions (CNVRs) by merging overlapping CNVs (30% of overlap threshold) detected in two or more genomes. In total 1271 CNVRs identified. When all CNVRs identified in the study were compared with the CNVRs in the DGV, 149 common (more than 2 incidences) CNVRs were novel, not found in DGV database. Like CNVs, CNVRs-losses were more frequent than CNVR-gains. Defined CNVRs encompassing 29.2Mb accounted for ≂f1% of the human genome. Total of 1029 NM numbered transcripts were located near or within the 1271 CNVRs. Through gene ontology (GO) analysis, putative target genes within the commonly gained or deleted region were categorized. Gene functions significantly enriched in the identified CNVRs include receptors for signal transduction pathways, transcription factors with nucleic acid binding proteins, defense/immunity molecules and regulatory molecule related functions involved in developmental processes. Hierarchical clustering of pooled datasets clearly distinguished IgG Kappa from Lambda subtypes. Genotype distributions for 32,110 non-synonymous SNPs in MM were also examined and compared to two lab-specific as well as 90 Korean HapMap samples as control reference. Conclusions: Power of High-resolution single-nucleotide polymorphism (SNP) array-based analysis allowed us a high incidence of gains and losses in MM patients. Many of those detectable legions were previously unidentified cryptic chromosomal aberrations. Although results reveals high degrees of heterogeneity in the genomic alterations detectable in MM, genes of the signal transduction pathway and defense/immunity processes were the most frequently altered targets whose deregulation may play a role in the pathogenesis of MM. CNVs/CNVRs identified in the study will be solid resources for investigating chromosomal aberrations in MM and its potential association with MM. Disclosures: No relevant conflicts of interest to declare.

Prenatal Diagnosis of DNA Copy Number Variations by Genomic Single-Nucleotide Polymorphism Array in Fetuses with Congenital Heart Defects

2015 ◽  
Vol 39 (1) ◽  
pp. 64-73 ◽  
Author(s):  
Shaohua Tang ◽  
Jiaojiao Lv ◽  
Xiangnan Chen ◽  
Lili Bai ◽  
Huanzheng Li ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Copy Number ◽  
Congenital Heart ◽  
Heart Defects ◽  
Snp Array ◽  
Genetic Diagnosis ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Prenatal Diagnostic ◽  
Clinically Significant

Objectives: To evaluate the usefulness of single-nucleotide polymorphism (SNP) array for prenatal genetic diagnosis of congenital heart defect (CHD), we used this approach to detect clinically significant copy number variants (CNVs) in fetuses with CHDs. Methods: A HumanCytoSNP-12 array was used to detect genomic samples obtained from 39 fetuses that exhibited cardiovascular abnormalities on ultrasound and had a normal karyotype. The relationship between CNVs and CHDs was identified by using genotype-phenotype comparisons and searching of chromosomal databases. All clinically significant CNVs were confirmed by real-time PCR. Results: CNVs were detected in 38/39 (97.4%) fetuses: variants of unknown significance were detected in 2/39 (5.1%), and clinically significant CNVs were identified in 7/39 (17.9%). In 3 of the 7 fetuses with clinically significant CNVs, 3 rare and previously undescribed CNVs were detected, and these CNVs encompassed the CHD candidate genes FLNA (Xq28 dup), BCOR (Xp11.4 dup), and RBL2 (16q12.2 del). Conclusion: Compared with conventional cytogenetic genomics, SNP array analysis provides significantly improved detection of submicroscopic genomic aberrations in pregnancies with CHDs. Based on these results, we propose that genomic SNP array is an effective method which could be used in the prenatal diagnostic test to assist genetic counseling for pregnancies with CHDs.

scholarly journals Allelic alterations in pancreatic endocrine tumors identified by genome-wide single nucleotide polymorphism analysis

2007 ◽  
Vol 14 (2) ◽  
pp. 483-492 ◽  
Author(s):  
Yasuhiko Nagano ◽  
Do Ha Kim ◽  
Li Zhang ◽  
Jill A White ◽  
James C Yao ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Chromosomal Aberrations ◽  
Copy Number ◽  
Snp Array ◽  
Endocrine Tumors ◽  
Copy Number Alterations ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Pancreatic Endocrine Tumors ◽  
Genome Wide

Pancreatic endocrine tumors (PETs) are uncommon and the genetic alterations in these indolent tumors are not well characterized. Chromosomal imbalances are frequent in tumors but PETs have not been studied by high-density single nucleotide polymorphism (SNP) array. We used genome-wide high-density SNP array analysis to detect copy number alterations using matched tumor and non-neoplastic tissue samples from 15 patients with PETs. In our study, whole or partial loss of chromosomes 1, 3, 11, 22 was present in 40, 47, 53, 40% of tumors respectively, and gain of chromosomes 5, 7, 12, 14, 17, and 20 was present in 47, 60, 47, 53, 53, and 47% of tumors respectively. One tumor had loss of heterozygosity of chromosome 3 and another of chromosome 22 without copy number alterations, suggesting uniparental disomy due to non-disjunction and deletion or to chromosomal recombination. Chromosomal aberrations of the autosomal chromosomes were correlated with chromosomal loss or gain of other chromosomes (r>0.5, P<0.5). About 60% of PETs had high allelic imbalances (AI) defined by more than four chromosomal aberrations, and 40% of tumors had low AI. The PETs with high AI were larger: the mean tumor size with high AI was 5.4 ± 3.1 cm compared with 2.3 ± 1.3 cm for low AI (P = 0.03). Our study shows that genome-wide allelotyping is a powerful new tool for the analysis of AI in PETs.

scholarly journals Prenatal diagnosis of 22q11.2 copy number abnormalities in fetuses via single nucleotide polymorphism array

2020 ◽  
Vol 47 (10) ◽  
pp. 7529-7535
Author(s):  
Meiying Cai ◽  
Na Lin ◽  
Linjuan Su ◽  
Xiaoqing Wu ◽  
Xiaorui Xie ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Prenatal Diagnosis ◽  
Copy Number ◽  
Single Nucleotide Polymorphism Array ◽  
Snp Array ◽  
Cardiovascular Malformations ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Ultrasound Findings ◽  
Kidney Malformations

Abstract The q11.2 region on chromosome 22 contains numerous low-copy repeats that lead to deleted or duplicated regions in the chromosome, thereby resulting in different syndromes characterized by intellectual disabilities or congenital anomalies. The association between patient phenotypes and 22q11.2 copy number abnormalities has been previously described in postnatal cases; however, these features have not been systematically evaluated in prenatal cases because of limitations in phenotypic identification in prenatal testing. In this study, we investigated the detection rate of 22q11.2 copy number abnormalities in 2500 fetuses using single nucleotide polymorphism (SNP) array and determined the common abnormal ultrasound findings in fetuses carrying the 22q11.2 copy number abnormalities. The 22q11.2 copy number abnormalities were identified in 13 fetuses with cardiovascular malformations (6/13), kidney malformations (3/13), isolated ultrasound markers (3/13), or high-risk Down syndrome based on maternal serum screening (1/13). Approximately 0.5% (13/2500) of the fetuses harbored 22q11.2 copy number abnormalities. The most frequent ultrasound findings in fetuses with these abnormalities were cardiovascular malformations, followed by kidney malformations and isolated ultrasound markers. Prenatal diagnosis of these genetic abnormalities allows for the delineation of differential diagnoses, characterization of a wide spectrum of associated malformations, and determination of associations that exist between prenatal diagnosis and obstetrical outcomes.

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 (&lt;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.

scholarly journals Detection of copy number variation associated with ventriculomegaly in fetuses using single nucleotide polymorphism arrays

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Huili Xue ◽  
Aili Yu ◽  
Na Lin ◽  
Xuemei Chen ◽  
Min Lin ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Copy Number ◽  
Snp Array ◽  
Copy Number Variations ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Group I ◽  
Number Variation ◽  
Fetal Ventriculomegaly ◽  
Cns Anomalies

AbstractEtiopathogenesis of fetal ventriculomegaly is poorly understood. Associations between fetal isolated ventriculomegaly and copy number variations (CNVs) have been previously described. We investigated the correlations between fetal ventriculomegaly—with or without other ultrasound anomalies—and chromosome abnormalities. 222 fetuses were divided into four groups: (I) 103 (46.4%) cases with isolated ventriculomegaly, (II) 41 (18.5%) cases accompanied by soft markers, (III) 33 (14.9%) cases complicated with central nervous system (CNS) anomalies, and (IV) 45 (20.3%) cases with accompanying anomalies. Karyotyping and single nucleotide polymorphism (SNP) array were used in parallel. Karyotype abnormalities were identified in 15/222 (6.8%) cases. Karyotype abnormalities in group I, II, III, and IV were 4/103 (3.9%), 2/41 (4.9%), 4/33 (12.1%), and 5/45 (11.1%), respectively. Concerning the SNP array analysis results, 31/222 (14.0%) were CNVs, CNVs in groups I, II, III, and IV were 11/103 (10.7%), 6/41 (14.6%), 9/33 (27.3%), and 5/45 fetuses (11.1%), respectively. Detections of clinical significant CNVs were higher in non-isolated ventriculomegaly than in isolated ventriculomegaly (16.81% vs 10.7%, P = 0.19). SNP arrays can effectively identify CNVs in fetuses with ventriculomegaly and increase the abnormal chromosomal detection rate by approximately 7.2%, especially ventriculomegaly accompanied by CNS anomalies.

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