Detection of copy number variations in melanocytic lesions utilising array based comparative genomic hybridisation

Pathology ◽  
2017 ◽  
Vol 49 (3) ◽  
pp. 285-291 ◽  
Author(s):  
Nima Mesbah Ardakani ◽  
Carla Thomas ◽  
Cleo Robinson ◽  
Kym Mina ◽  
Nathan Tobias Harvey ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Variations ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Melanocytic Lesions

Clinical Implications of Chromosome 16 Copy Number Variation

2021 ◽  
pp. 1-9
Author(s):  
Emine Ikbal Atli ◽  
Sinem Yalcintepe ◽  
Engin Atli ◽  
Selma Demir ◽  
Cisem Mail ◽  
...  
Keyword(s):  
Copy Number ◽  
Clinical Presentation ◽  
Phenotypic Variability ◽  
Copy Number Variations ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Chromosome 16 ◽  
Genomic Changes ◽  
Number Variation ◽  
Nonallelic Homologous Recombination

Chromosome 16 is one of the gene-rich chromosomes; however, approximately 10% of the chromosome 16 sequence is composed of segmental copies, which renders this chromosome instable and predisposes it to rearrangements via frequent nonallelic homologous recombination. Microarray technologies have enabled the analysis of copy number variations (CNV), which may be associated with the risk of developing complex diseases. Through comparative genomic hybridisation in 1,298 patients, we detected 18 cases with chromosome 16 CNV. We identified 2recurrent CNV regions, including 1 at 16p13.11 in 4 patients and another at 16p11.2 in 7 patients. We also detected atypical chromosome 16 rearrangements in 7 patients. Furthermore, we noted an increased frequency of co-occurring genomic changes, supporting the two-hit hypothesis to explain the phenotypic variability in the clinical presentation of CNV syndromes. Our findings can contribute to the creation of a chromosome 16 disease map based on regions that may be associated with disease development.

scholarly journals Genome-wide copy number variations as molecular diagnostic tool for cutaneous intermediate melanocytic lesions: a systematic review and individual patient data meta-analysis

2021 ◽  
Author(s):  
Chiel F. Ebbelaar ◽  
Anne M. L. Jansen ◽  
Lourens T. Bloem ◽  
Willeke A. M. Blokx
Keyword(s):  
Systematic Review ◽  
Sensitivity And Specificity ◽  
Copy Number ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Copy Number Variations ◽  
Patient Data ◽  
Melanocytic Lesions ◽  
Genome Wide ◽  
Malignant Lesions

AbstractCutaneous intermediate melanocytic neoplasms with ambiguous histopathological features are diagnostically challenging. Ancillary cytogenetic techniques to detect genome-wide copy number variations (CNVs) might provide a valuable tool to allow accurate classification as benign (nevus) or malignant (melanoma). However, the CNV cut-off value to distinguish intermediate lesions from melanoma is not well defined. We performed a systematic review and individual patient data meta-analysis to evaluate the use of CNVs to classify intermediate melanocytic lesions. A total of 31 studies and 431 individual lesions were included. The CNV number in intermediate lesions (median 1, interquartile range [IQR] 0–2) was significantly higher (p<0.001) compared to that in benign lesions (median 0, IQR 0–1) and lower (p<0.001) compared to that in malignant lesions (median 6, IQR 4–11). The CNV number displayed excellent ability to differentiate between intermediate and malignant lesions (0.90, 95% CI 0.86–0.94, p<0.001). Two CNV cut-off points demonstrated a sensitivity and specificity higher than 80%. A cut-off of ≥3 CNVs corresponded to 85% sensitivity and 84% specificity, and a cut-off of ≥4 CNVs corresponded to 81% sensitivity and 91% specificity, respectively. This individual patient data meta-analysis provides a comprehensive overview of CNVs in cutaneous intermediate melanocytic lesions, based on the largest pooled cohort of ambiguous melanocytic neoplasms to date. Our meta-analysis suggests that a cut-off of ≥3 CNVs might represent the optimal trade-off between sensitivity and specificity in clinical practice to differentiate intermediate lesions from melanoma.

Development of a genomic predictive model for cholangiocarcinoma using copy number alteration data

2021 ◽  
pp. jclinpath-2020-207346
Author(s):  
Inês Tavares ◽  
Ricardo Martins ◽  
Ilda Patrícia Ribeiro ◽  
Luísa Esteves ◽  
Francisco Caramelo ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Copy Number ◽  
Patient Management ◽  
Copy Number Alteration ◽  
Comparative Genomic Hybridisation ◽  
Support Vector ◽  
Comparative Genomic ◽  
Support Vector Machine Algorithm ◽  
Rare Tumour ◽  
Genomic Model

AimsCholangiocarcinoma (CC) is a rare tumour arising from the biliary tract epithelium. The aim of this study was to perform a genomic characterisation of CC tumours and to implement a model to differentiate extrahepatic (ECC) and intrahepatic (ICC) cholangiocarcinoma.MethodsDNA extracted from tumour samples of 23 patients with CC, namely 10 patients with ECC and 13 patients with ICC, was analysed by array comparative genomic hybridisation. A support vector machine algorithm for classification was applied to the genomic data to distinguish between ICC and ECC. A survival analysis comparing both groups of patients was also performed.ResultsWith these whole genome results, we observed several common alterations between tumour samples of the same CC anatomical type, namely gain of Xp and loss of 3p, 11q11, 14q, 16q, Yp and Yq in ICC tumours, and gain of 16p25.3 and loss of 3q26.1, 6p25.3–22.3, 12p13.31, 17p, 18q and Yp in ECC tumours. Gain of 2q37.3 was observed in the samples of both tumour subtypes, ICC and ECC. The developed genomic model comprised four chromosomal regions that seem to enable the distinction between ICC and ECC, with an accuracy of 71.43% (95% CI 43% to 100%). Survival analysis revealed that in our cohort, patients with ECC survived on average 8 months less than patients with ICC.ConclusionsThis genomic characterisation and the introduction of genomic models to clinical practice could be important for patient management and for the development of targeted therapies. The power of this genomic model should be evaluated in other CC populations.

scholarly journals Multiplex ligation-dependent probe amplification – a short overview

2020 ◽  
Vol 28 (2) ◽  
pp. 123-131
Author(s):  
Valeriu Moldovan ◽  
Elena Moldovan
Keyword(s):  
Copy Number ◽  
Genetic Disorders ◽  
Cost Effective ◽  
Copy Number Variations ◽  
Comparative Genomic ◽  
Gene Deletions ◽  
Conventional Cytogenetic Analysis ◽  
Main Technique ◽  
Cost Effective Technique ◽  
Dependent Probe

AbstractMultiplex Ligation-dependent Probe Amplification is a technique proposed for the detection of deletions or duplications that may lead to copy number variations in genomic DNA, mainly due to its higher resolution, and shorter overall diagnosis time, when compared with techniques traditionally used, namely karyotyping, fluorescence in situ hybridization, and array comparative genomic hybridization. Multiplex Ligation-dependent Probe Amplification is a fast (about 2 days), useful and cost-effective technique, being suitable for the diagnosis of hereditary conditions caused by complete or partial gene deletions or duplications, as these conditions are either more difficult or impossible to be diagnosed by other techniques, such as PCR, Real-Time PCR, or sequencing (Sanger or Next Generation). Due to its numerous advantages over conventional cytogenetic analysis techniques, Multiplex Ligation-dependent Probe Amplification could be used in the near future as the main technique for the molecular investigation of genetic conditions caused by copy number variations, in both rare and complex genetic disorders.

scholarly journals Bayesian Disease Classification Using Copy Number Data

2014 ◽  
Vol 13s2 ◽  
pp. CIN.S13785 ◽  
Author(s):  
Subharup Guha ◽  
Yuan Ji ◽  
Veerabhadran Baladandayuthapani
Keyword(s):  
Copy Number ◽  
Copy Number Variations ◽  
Disease Classification ◽  
Classification Model ◽  
Basic Knowledge ◽  
Comparative Genomic ◽  
Breast Cancer Dataset ◽  
Disease Category ◽  
Cancer Dataset ◽  
Disease States

DNA copy number variations (CNVs) have been shown to be associated with cancer development and progression. The detection of these CNVs has the potential to impact the basic knowledge and treatment of many types of cancers, and can play a role in the discovery and development of molecular-based personalized cancer therapies. One of the most common types of high-resolution chromosomal microarrays is array-based comparative genomic hybridization (aCGH) methods that assay DNA CNVs across the whole genomic landscape in a single experiment. In this article we propose methods to use aCGH profiles to predict disease states. We employ a Bayesian classification model and treat disease states as outcome, and aCGH profiles as covariates in order to identify significant regions of the genome associated with disease subclasses. We propose a principled two-stage method where we first make inferences on the underlying copy number states associated with the aCGH emissions based on hidden Markov model (HMM) formulations to account for serial dependencies in neighboring probes. Subsequently, we infer associations with disease outcomes, conditional on the copy number states, using Bayesian linear variable selection procedures. The selected probes and their effects are parameters that are useful for predicting the disease categories of any additional individuals on the basis of their aCGH profiles. Using simulated datasets, we investigate the method's accuracy in detecting disease category. Our methodology is motivated by and applied to a breast cancer dataset consisting of aCGH profiles assayed on patients from multiple disease subtypes.

Autism spectrum mixed neurodevelopmental disorder associated with 6q27 deletion and multiple copies within 20q11.23: a case study

2014 ◽  
Vol 8 (3) ◽  
pp. 210-215
Author(s):  
Stephen Hopkins ◽  
Jeremy Turk ◽  
Adeniyi Daramola ◽  
Marinos Kyriakopoulos
Keyword(s):  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Content Type ◽  
Effective Strategies ◽  
Wide Range ◽  
Multiple Copies

Purpose – Copy Number Variations (CNVs) are not infrequently observed in aberrant neurodevelopment. CNVs can alter gene expression and have been linked to a wide range of neuropsychiatric disorders. The purpose of this case study is to report the association of CNVs with a mixed neurodevelopmental disorder. Design/methodology/approach – Array-Comparative Genomic Hybridisation analysis was carried out in a case of an eight-year-old boy presenting with a mixed neurodevelopmental disorder including autism spectrum disorder, intellectual disability, tic disorder, anxiety and severe aggression. The child's parents also underwent the same investigation. Findings – A 6q27 deletion and multiple copies within 20q11.23 were identified. The boy's father shared the 6q27 deletion and his mother also had multiple copies within 20q11.23. Originality/value – This is the first report linking the combination of 6p27 and 20q11 CNVs with a mixed neurodevelopmental presentation. Identifying CNVs that may underlie aberrant neurodevelopment is likely to assist in unravelling the aetiology of neurodevelopmental and psychiatric disorders and lead to more effective strategies for their characterisation and management.

Overall Genomic Pattern Is a Predictor of Outcome in Neuroblastoma

2009 ◽  
Vol 27 (7) ◽  
pp. 1026-1033 ◽  
Author(s):  
Isabelle Janoueix-Lerosey ◽  
Gudrun Schleiermacher ◽  
Evi Michels ◽  
Véronique Mosseri ◽  
Agnès Ribeiro ◽  
...  
Keyword(s):  
Copy Number ◽  
Prognostic Significance ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Comparative Genomic ◽  
Mycn Amplification ◽  
Clinical Markers ◽  
Prognostic Information ◽  
Stage 4 ◽  
Risk Of Relapse

Purpose For a comprehensive overview of the genetic alterations of neuroblastoma, their association and clinical significance, we conducted a whole-genome DNA copy number analysis. Patients and Methods A series of 493 neuroblastoma (NB) samples was investigated by array-based comparative genomic hybridization in two consecutive steps (224, then 269 patients). Results Genomic analysis identified several types of profiles. Tumors presenting exclusively whole-chromosome copy number variations were associated with excellent survival. No disease-related death was observed in this group. In contrast, tumors with any type of segmental chromosome alterations characterized patients with a high risk of relapse. Patients with both numerical and segmental abnormalities clearly shared the higher risk of relapse of segmental-only patients. In a multivariate analysis, taking into account the genomic profile, but also previously described individual genetic and clinical markers with prognostic significance, the presence of segmental alterations with (HR, 7.3; 95% CI, 3.7 to 14.5; P < .001) or without MYCN amplification (HR, 4.5; 95% CI, 2.4 to 8.4; P < .001) was the strongest predictor of relapse; the other significant variables were age older than 18 months (HR, 1.8; 95% CI, 1.2 to 2.8; P = .004) and stage 4 (HR, 1.8; 95% CI, 1.2 to 2.7; P = .005). Finally, within tumors showing segmental alterations, stage 4, age, MYCN amplification, 1p and 11q deletions, and 1q gain were independent predictors of decreased overall survival. Conclusion The analysis of the overall genomic pattern, which probably unravels particular genomic instability mechanisms rather than the analysis of individual markers, is essential to predict relapse in NB patients. It adds critical prognostic information to conventional markers and should be included in future treatment stratification.

scholarly journals Motor Chip: A Comparative Genomic Hybridization Microarray for Copy-Number Mutations in 245 Neuromuscular Disorders

2011 ◽  
Vol 57 (11) ◽  
pp. 1584-1596 ◽  
Author(s):  
Giulio Piluso ◽  
Manuela Dionisi ◽  
Francesca Del Vecchio Blanco ◽  
Annalaura Torella ◽  
Stefania Aurino ◽  
...  
Keyword(s):  
Comparative Genomic Hybridization ◽  
Copy Number ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Copy Number Variations ◽  
Comparative Genomic ◽  
Specific Gene ◽  
Disease Genes ◽  
Genomic Hybridization ◽  
Gene Coverage

BACKGROUND Array-based comparative genomic hybridization (aCGH) is a reference high-throughput technology for detecting large pathogenic or polymorphic copy-number variations in the human genome; however, a number of quantitative monogenic mutations, such as smaller heterozygous deletions or duplications, are usually missed in most disease genes when proper multiplex ligation-dependent probe assays are not performed. METHODS We developed the Motor Chip, a customized CGH array with exonic coverage of 245 genes involved in neuromuscular disorders (NMDs), as well as 180 candidate disease genes. We analyzed DNA samples from 26 patients with known deletions or duplications in NMDs, 11 patients with partial molecular diagnoses, and 19 patients with a clinical diagnosis alone. RESULTS The Motor Chip efficiently confirmed and refined the copy-number mutations in all of the characterized patients, even when only a single exon was involved. In noncharacterized or partially characterized patients, we found deletions in the SETX (senataxin), SGCG [sarcoglycan, gamma (35kDa dystrophin-associated glycoprotein)], and LAMA2 (laminin, alpha 2) genes, as well as duplications involving LAMA2 and the DYSF [dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive)] locus. CONCLUSIONS The combination of exon-specific gene coverage and optimized platform and probe selection makes the Motor Chip a complementary tool for molecular diagnosis and gene investigation in neuromuscular diseases.

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