MPTH-40. COPY NUMBER ALTERATIONS IN PLEOMORPHIC XANTHOASTROCYTOMA AND ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA: CHARACTERIZATION OF 40 CASES BY SNP ARRAY

Background and Objectives: Mycosis fungoides (MF) and large plaque parapsoriasis (LPP) evolution provide intriguing data and are the cause of numerous debates. The diagnosis of MF and LPP is associated with confusion and imprecise definition. Copy number alterations (CNAs) may play an essential role in the genesis of cancer out of genes expression dysregulation. Objectives: Due to the heterogeneity of MF and LPP and the scarcity of the cases, there are an exceedingly small number of studies that have identified molecular changes in these pathologies. We aim to identify and compare DNA copy number alterations and gene expression changes between MF and LPP to highlight the similarities and the differences between these pathologies. Materials and Methods: The patients were prospectively selected from University Clinic of Dermatology and Venereology Timișoara, Romania. From fresh frozen skin biopsies, we extracted DNA using single nucleotide polymorphism (SNP) data. The use of SNP array for copy number profiling is a promising approach for genome-wide analysis. Results: After reviewing each group, we observed that the histograms generated for chromosome 1–22 were remarkably similar and had a lot of CNAs in common, but also significant differences were seen. Conclusions: This study took a step forward in finding out the differences and similarities between MF and LPP, for a more specific and implicitly correct approach of the case. The similarity between these two pathologies in terms of CNAs is striking, emphasizing once again the difficulty of approaching and differentiating them.

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Screening and detection of chromosomal copy number alterations in the domestic horse using SNP‐array genotyping data

Animal Genetics ◽

10.1111/age.13077 ◽

2021 ◽

Author(s):

Y. Pirosanto ◽

N. Laseca ◽

M. Valera ◽

A. Molina ◽

M. Moreno‐Millán ◽

...

Keyword(s):

Copy Number ◽

Snp Array ◽

Domestic Horse ◽

Copy Number Alterations ◽

Chromosomal Copy Number ◽

Chromosomal Copy

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Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma

Cancers ◽

10.3390/cancers13020218 ◽

2021 ◽

Vol 13 (2) ◽

pp. 218

Author(s):

Aline Neves Araujo ◽

Cléber Pinto Camacho ◽

Thais Biude Mendes ◽

Susan Chow Lindsey ◽

Lais Moraes ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Copy Number ◽

Snp Array ◽

In Silico Analysis ◽

Pcr Analysis ◽

Copy Number Alterations ◽

Medullary Thyroid ◽

Thyroid C Cells ◽

Ajcc Staging

Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C-cells that can occur either in sporadic (70–80%) or hereditary (20–30%) form. In this study we aimed to identify recurrent copy number alterations (CNA) that might be related to the pathogenesis or progression of MTC. We used Affymetrix SNP array 6.0 on MTC and paired-blood samples to identify CNA using PennCNV and Genotyping Console software. The algorithms identified recurrent copy number gains in chromosomes 15q, 10q, 14q and 22q in MTC, whereas 4q cumulated losses. Coding genes were identified within CNA regions. The quantitative PCR analysis performed in an independent series of MTCs (n = 51) confirmed focal recurrent copy number gains encompassing the DLK1 (14q32.2) and AIFM3 (22q11.21) genes. Immunohistochemistry confirmed AIFM3 and DLK1 expression in MTC cases, while no expression was found in normal thyroid tissues and few MTC samples were found with normal copy numbers. The functional relevance of CNA was also assessed by in silico analysis. CNA status correlated with protein expression (DLK1, p = 0.01), tumor size (DLK1, p = 0.04) and AJCC staging (AIFM3p = 0.01 and DLK1p = 0.05). These data provide a novel insight into MTC biology, and suggest a common CNA landscape, regardless of if it is sporadic or hereditary MTC.

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Characterization of 9p21 copy number alterations in human melanoma by fluorescence in situ hybridization

Cancer Genetics and Cytogenetics ◽

10.1016/j.cancergencyto.2008.01.008 ◽

2008 ◽

Vol 182 (2) ◽

pp. 116-121 ◽

Cited By ~ 17

Author(s):

Zsuzsa Rákosy ◽

Laura Vízkeleti ◽

Szilvia Ecsedi ◽

Ágnes Bégány ◽

Gabriella Emri ◽

...

Keyword(s):

In Situ Hybridization ◽

Fluorescence In Situ Hybridization ◽

Copy Number ◽

Human Melanoma ◽

Copy Number Alterations

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Erratum to “A statistical method to detect chromosomal regions with DNA copy number alterations using SNP-array-based CGH data”

Computational Biology and Chemistry ◽

10.1016/j.compbiolchem.2005.05.002 ◽

2005 ◽

Vol 29 (3) ◽

pp. 258

Author(s):

Yinglei Lai ◽

Hongyu Zhao

Keyword(s):

Statistical Method ◽

Copy Number ◽

Snp Array ◽

Copy Number Alterations ◽

Dna Copy Number ◽

Dna Copy Number Alterations

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DNA Analysis by Restriction Enzyme (DARE) enables concurrent genomic and epigenomic characterization of single cells

Nucleic Acids Research ◽

10.1093/nar/gkz717 ◽

2019 ◽

Vol 47 (19) ◽

pp. e122-e122

Author(s):

Ramya Viswanathan ◽

Elsie Cheruba ◽

Lih Feng Cheow

Keyword(s):

Dna Methylation ◽

Restriction Enzyme ◽

Copy Number ◽

Dna Analysis ◽

Whole Genome Amplification ◽

Single Cells ◽

Whole Genome ◽

Copy Number Alterations ◽

Genome Wide

Abstract Genome-wide profiling of copy number alterations and DNA methylation in single cells could enable detailed investigation into the genomic and epigenomic heterogeneity of complex cell populations. However, current methods to do this require complex sample processing and cleanup steps, lack consistency, or are biased in their genomic representation. Here, we describe a novel single-tube enzymatic method, DNA Analysis by Restriction Enzyme (DARE), to perform deterministic whole genome amplification while preserving DNA methylation information. This method was evaluated on low amounts of DNA and single cells, and provides accurate copy number aberration calling and representative DNA methylation measurement across the whole genome. Single-cell DARE is an attractive and scalable approach for concurrent genomic and epigenomic characterization of cells in a heterogeneous population.

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

Blood ◽

10.1182/blood.v116.21.2721.2721 ◽

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.

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A comprehensive molecular characterization of the 8q22.2 region reveals the prognostic relevance of OSR2 mRNA in muscle invasive bladder cancer

PLoS ONE ◽

10.1371/journal.pone.0248342 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0248342

Author(s):

Daniel Uysal ◽

Karl-Friedrich Kowalewski ◽

Maximilian Christian Kriegmair ◽

Ralph Wirtz ◽

Zoran V. Popovic ◽

...

Keyword(s):

Bladder Cancer ◽

In Silico ◽

Copy Number ◽

In Silico Analysis ◽

Copy Number Alterations ◽

Muscle Invasive Bladder Cancer ◽

Mrna Gene ◽

Muscle Invasive ◽

Silico Analysis

Technological advances in molecular profiling have enabled the comprehensive identification of common regions of gene amplification on chromosomes (amplicons) in muscle invasive bladder cancer (MIBC). One such region is 8q22.2, which is largely unexplored in MIBC and could harbor genes with potential for outcome prediction or targeted therapy. To investigate the prognostic role of 8q22.2 and to compare different amplicon definitions, an in-silico analysis of 357 patients from The Cancer Genome Atlas, who underwent radical cystectomy for MIBC, was performed. Amplicons were generated using the GISTIC2.0 algorithm for copy number alterations (DNA_Amplicon) and z-score normalization for mRNA gene overexpression (RNA_Amplicon). Kaplan-Meier survival analysis, univariable, and multivariable Cox proportional hazard ratios were used to relate amplicons, genes, and clinical parameters to overall (OS) and disease-free survival (DFS). Analyses of the biological functions of 8q22.2 genes and genomic events in MIBC were performed to identify potential targets. Genes with prognostic significance from the in silico analysis were validated using RT-qPCR of MIBC tumor samples (n = 46). High 8q22.2 mRNA expression (RNA-AMP) was associated with lymph node metastases. Furthermore, 8q22.2 DNA and RNA amplified patients were more likely to show a luminal subtype (DNA_Amplicon_core: p = 0.029; RNA_Amplicon_core: p = 0.01). Overexpression of the 8q22.2 gene OSR2 predicted shortened DFS in univariable (HR [CI] 1.97 [1.2; 3.22]; p = 0.01) and multivariable in silico analysis (HR [CI] 1.91 [1.15; 3.16]; p = 0.01) and decreased OS (HR [CI] 6.25 [1.37; 28.38]; p = 0.0177) in RT-qPCR data analysis. Alterations in different levels of the 8q22.2 region are associated with manifestation of different clinical characteristics in MIBC. An in-depth comprehensive molecular characterization of genomic regions involved in cancer should include multiple genetic levels, such as DNA copy number alterations and mRNA gene expression, and could lead to a better molecular understanding. In this study, OSR2 is identified as a potential biomarker for survival prognosis.

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Amplification of the EGFR and CCND1 Are Coordinated and Play Important Roles in the Progression of Oral Squamous Cell Carcinomas

Cancers ◽

10.3390/cancers11060760 ◽

2019 ◽

Vol 11 (6) ◽

pp. 760 ◽

Cited By ~ 6

Author(s):

Huei-Tzu Chien ◽

Sou-De Cheng ◽

Chun-Ta Liao ◽

Hung-Ming Wang ◽

Shiang-Fu Huang

Keyword(s):

Squamous Cell ◽

Tumor Suppressor Genes ◽

Copy Number ◽

Clinical Stage ◽

Copy Number Alterations ◽

Suppressor Genes ◽

Common Cancer ◽

Genome Wide

Oral squamous cell carcinoma (OSCC) is a common cancer in Taiwan and worldwide. To provide some clues for clinical management of OSCC, 72 advanced-stage OSCCs were analyzed using two microarray platforms (26 cases with Affymetrix 500 K and 46 cases with Affymetrix SNP 6.0). Genomic identification of significant targets in cancer analyses were used to identify significant copy number alterations (CNAs) using a q-value cutoff of 0.25. Among the several significant regions, 12 CNAs were common between these two platforms. Two gain regions contained the well-known oncogenes EGFR (7p11.2) and CCND1 (11q13.3) and several known cancer suppressor genes, such as FHIT (3p14.2–p12.1), FAT1 (4q35.1), CDKN2A (9p21.3), and ATM (11q22.3–q24.3), reside within the 10 deletion regions. Copy number gains of EGFR and CCND1 were further confirmed by fluorescence in situ hybridization and TaqMan CN assay, respectively, in 257 OSCC cases. Our results indicate that EGFR and CCND1 CNAs are significantly associated with clinical stage, tumor differentiation, and lymph node metastasis. Furthermore, EGFR and CCND1 CNAs have an additive effect on OSCC tumor progression. Thus, current genome-wide CNA analysis provides clues for future characterization of important oncogenes and tumor suppressor genes associated with the behaviors of the disease.

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SNP Array Profiling of Childhood Adrenocortical Tumors Reveals Distinct Pathways of Tumorigenesis and Highlights Candidate Driver Genes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-1184 ◽

2012 ◽

Vol 97 (7) ◽

pp. E1284-E1293 ◽

Cited By ~ 29

Author(s):

Eric Letouzé ◽

Roberto Rosati ◽

Heloisa Komechen ◽

Mabrouka Doghman ◽

Laetitia Marisa ◽

...

Keyword(s):

Copy Number ◽

Tp53 Mutation ◽

Snp Array ◽

Genetic Alterations ◽

Chromosome 17 ◽

Comparative Genomic ◽

Copy Number Alterations ◽

Wild Type ◽

Driver Genes ◽

Adrenocortical Tumors

Abstract Context: Childhood adrenocortical tumors (ACT) are rare malignancies, except in southern Brazil, where a higher incidence rate is associated to a high frequency of the founder R337H TP53 mutation. To date, copy number alterations in these tumors have only been analyzed by low-resolution comparative genomic hybridization. Objective: We analyzed an international series of 25 childhood ACT using high-resolution single nucleotide polymorphism arrays to: 1) detect focal copy number alterations highlighting candidate driver genes; and 2) compare genetic alterations between Brazilian patients carrying the R337H TP53 mutation and non-Brazilian patients. Results: We identified 16 significantly recurrent chromosomal alterations (q-value < 0.05), the most frequent being −4q34, +9q33-q34, +19p, loss of heterozygosity (LOH) of chromosome 17 and 11p15. Focal amplifications and homozygous deletions comprising well-known oncogenes (MYC, MDM2, PDGFRA, KIT, MCL1, BCL2L1) and tumor suppressors (TP53, RB1, RPH3AL) were identified. In addition, eight focal deletions were detected at 4q34, defining a sharp peak region around the noncoding RNA LINC00290 gene. Although non-Brazilian tumors with a mutated TP53 were similar to Brazilian tumors, those with a wild-type TP53 displayed distinct genomic profiles, with significantly fewer rearrangements (P = 0.019). In particular, three alterations (LOH of chromosome 17, +9q33-q34, and −4q34) were significantly more frequent in TP53-mutated samples. Finally, two of four TP53 wild-type tumors displayed as sole rearrangement a copy-neutral LOH of the imprinted region at 11p15, supporting a major role for this region in ACT development. Conclusions: Our findings highlight potential driver genes and cellular pathways implicated in childhood ACT and demonstrate the existence of different oncogenic routes in this pathology.

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