scholarly journals High‐resolution genomic copy number profiling of primary intraocular lymphoma by single nucleotide polymorphism microarrays

2014 ◽  
Vol 105 (5) ◽  
pp. 592-599 ◽  
Author(s):  
Ludan Wang ◽  
Aiko Sato‐Otsubo ◽  
Sunao Sugita ◽  
Hiroshi Takase ◽  
Manabu Mochizuki ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
High Resolution ◽  
Copy Number ◽  
Intraocular Lymphoma ◽  
Primary Intraocular Lymphoma ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genomic Copy Number ◽  
Genomic Copy

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.

High Resolution Genomic Profiling Using Single Nucleotide Polymorphism Microarrays Reveals Novel Genomic Lesions in Hairy Cell Leukaemia and Hairy-Cell Leukaemia Variant

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3136-3136
Author(s):  
Sarah L Hockley ◽  
Monica Else ◽  
Paola E Leone ◽  
Brian A Walker ◽  
Alison Morilla ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
High Resolution ◽  
Copy Number ◽  
Hairy Cell Leukaemia ◽  
Cell Leukaemia ◽  
Hairy Cell ◽  
Nucleotide Polymorphism ◽  
Chromosome 5 ◽  
Single Nucleotide ◽  
Minimal Region

Abstract Hairy-cell leukaemia (HCL) is a rare B-cell disorder, with a variant form (HCL-v), which differs from the former in morphology, immunophenotype, clinical behaviour and response to treatment. Whilst HCL is highly sensitive to purine analogues, HCL-v patients do not respond to these treatments and have a median survival of only 7 years compared to over 20 years in HCL. The relationship between these two disorders is yet to be determined and the molecular mechanisms underlying them are still largely unknown. Genomic studies are limited due to the rarity of the disease and have mainly been performed at the cytogenetic level. We have used single nucleotide polymorphism (SNP) arrays to examine DNA copy number changes and loss of heterozygosity (LOH) in 14 HCL and 15 HCL-v cases with the aim of finding genetic markers that may distinguish both disease types and can explain their different clinical outcome. DNA extracted from PBMC samples enriched for tumour cells (HC >84%) was interrogated using the Affymetrix Human Mapping 500K Array Set. Data were analysed using CNAG 2.0 and dCHIP 2006 to identify regions of genomic imbalance and LOH by comparison to a set of 25 normal controls. DNA copy number abnormalities (excluding the IGH and IGL heterogeneic loci) were identified in 11/14 (78%) HCL and 13/15 (87%) HCL-v cases. The median number of lesions per patient in HCL (2.5, range=0–14) was half that observed for HCL-v (5, range=0–34) (p=0.1, not significant) with 3/15 cases of HCL-v exhibiting more than 20 aberrations. The most significant difference between HCL and HCL-v was the occurrence of deletions on 17p, involving monoallelic loss of TP53. Such losses were evident in 33% (5/15) of HCL-v cases compared to 0% of HCL cases (p=0.02). Sequencing analysis detected mutations in the non-deleted allele in 3/5 of these cases, suggesting biallelic loss of TP53 function. Other frequent events were present in both HCL and HCL-v and included gains on chromosome 5 (1/14 HCL and 5/15 HCL-v) and deletions on 7q (3/14 HCL and 3/15 HCL-v) and 14q (2/14 HCL and 1/15 HCL-v). Similar aberrations have been detected in previous cytogenetic studies of typical HCL but the high resolution of the SNP arrays has allowed us to further define these regions of imbalance in both disorders. Chromosome 5 abnormalities included trisomy 5 in two cases and a minimal region of gain, 18.9 Mb in size (5q34–q35.3), was present in 4/6 cases. The cases exhibiting 7q deletions allowed the minimal region to be further defined to 4.1 Mb (7q31.31–q31.33), a region containing approximately 25 known genes. Deletion of 14q24.1–q32.13 was seen in two HCL cases, therefore further minimising the 14q22–q32 region identified previously. One HCL-v case exhibited an interesting region of deletion at 14q32.32, consisting of a focal homozygous deletion flanked by hemizygous loss, containing candidate tumour suppressor genes that may be involved in HCL-v pathogenesis. In addition to these larger lesions, focal gains, harbouring only a single gene, were identified in both disorders at 19p13.2 (3/14 HCL, 3/15 HCL-v), 20p13 (4/14 HCL, 3/15 HCL-v) and 17q21.2 (4/16 HCL and 5/15 HCL-v). High-resolution copy number analyses allow the identification of novel genetic lesions in HCL and HCL-v and further define known cytogenetic aberrations. Our data show that HCL and HCL-v are generally similar at the genomic level but can be distinguished based on 17p deletions, suggesting that biallelic loss of TP53 may contribute to the greater genomic instability and to the aggressiveness of HCL-v. Other HCL-v cases may carry aberrations of other genes involved in DNA damage/repair pathways aside from TP53 and will be investigated.

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