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CGH


Figure 1. Principle of chromosomal CGH analysis. By Michael Baudis (http://www.progenetix.net)
Source/licence: http://en.wikipedia.org/wiki/File:CGH_schema.jpg

Comparative Genomic Hybridization (CGH): "A method for comparing two sets of chromosomal DNA by analyzing differences in the copy number and location of specific sequences. It is used to look for large sequence changes such as deletions, duplications, amplifications, or translocations." (MeSH 2013)

Array Comparative Genomic Hybridization (aCGH)

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Recent Publications: CGH / aCGH

Laczmanska I, Skiba P, Karpinski P, et al.
Customized Array Comparative Genomic Hybridization Analysis of 25 Phosphatase-encoding Genes in Colorectal Cancer Tissues.
Cancer Genomics Proteomics. 2017; 14(1):69-74 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: Molecular mechanisms of alterations in protein tyrosine phosphatases (PTPs) genes in cancer have been previously described and include chromosomal aberrations, gene mutations, and epigenetic silencing. However, little is known about small intragenic gains and losses that may lead to either changes in expression or enzyme activity and even loss of protein function.
MATERIALS AND METHODS: The aim of this study was to investigate 25 phosphatase genes using customized array comparative genomic hybridization in 16 sporadic colorectal cancer tissues.
RESULTS: The analysis revealed two unique small alterations: of 2 kb in PTPN14 intron 1 and of 1 kb in PTPRJ intron 1. We also found gains and losses of whole PTPs gene sequences covered by large chromosome aberrations.
CONCLUSION: In our preliminary studies using high-resolution custom microarray we confirmed that PTPs are frequently subjected to whole-gene rearrangements in colorectal cancer, and we revealed that non-polymorphic intragenic changes are rare.

Naka T, Hatanaka Y, Marukawa K, et al.
Comparative genetic analysis of a rare synchronous collision tumor composed of malignant pleural mesothelioma and primary pulmonary adenocarcinoma.
Diagn Pathol. 2016; 11:38 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Although asbestos acts as a potent carcinogen in pleural mesothelial and pulmonary epithelial cells, it still remains unclear whether asbestos causes specific and characteristic gene alterations in these different kinds of target cells, because direct comparison in an identical patient is not feasible. We experienced a rare synchronous collision tumor composed of malignant pleural mesothelioma (MPM) and primary pulmonary adenocarcinoma (PAC) in a 77-year-old man with a history of long-term smoking and asbestos exposure, and compared the DNA copy number alteration (CNA) and somatic mutation in these two independent tumors.
METHODS: Formalin-fixed paraffin-embedded (FFPE) tissues of MPM and PAC lesions from the surgically resected specimen were used. Each of these MPM and PAC lesions exhibited a typical histology and immunophenotype. CNA analysis using SNP array was performed using the Illumina Human Omni Express-12_FFPE (Illumina, San Diego, CA, USA) with DNA extracts from each lesion. Somatic mutation analysis using next-generation sequencing was performed using the TruSeq Amplicon Cancer Panel (Illumina).
RESULTS: The CNA analysis demonstrated a marked difference in the frequency of gain and loss between MPM and PAC. In PAC, copy number (CN) gain was detected more frequently and widely than CN loss, whereas in MPM there was no such obvious difference. PAC did not harbor CNAs that have been identified in asbestos-associated lung cancer, but did harbor some of the CNAs associated with smoking. MPM exhibited CN loss at 9p21.2-3, which is the most common genetic alteration in mesothelioma.
CONCLUSION: In this particular case, asbestos exposure may not have played a primary role in PAC carcinogenesis, but cigarette smoking may have contributed more to the occurrence of CN gains in PAC. This comparative genetic analysis of two different lesions with same amount of asbestos exposure and cigarette smoke exposure has provided information on differences in the cancer genome related to carcinogenesis.

Shivakumar BM, Chakrabarty S, Rotti H, et al.
Comparative analysis of copy number variations in ulcerative colitis associated and sporadic colorectal neoplasia.
BMC Cancer. 2016; 16:271 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The incidence of and mortality from colorectal cancers (CRC) can be reduced by early detection. Currently there is a lack of established markers to detect early neoplastic changes. We aimed to identify the copy number variations (CNVs) and the associated genes which could be potential markers for the detection of neoplasia in both ulcerative colitis-associated neoplasia (UC-CRN) and sporadic colorectal neoplasia (S-CRN).
METHODS: We employed array comparative genome hybridization (aCGH) to identify CNVs in tissue samples of UC nonprogressor, progressor and sporadic CRC. Select genes within these CNV regions as a panel of markers were validated using quantitative real time PCR (qRT-PCR) method along with the microsatellite instability (MSI) in an independent cohort of samples. Immunohistochemistry (IHC) analysis was also performed.
RESULTS: Integrated analysis showed 10 overlapping CNV regions between UC-Progressor and S-CRN, with the 8q and 12p regions showing greater overlap. The qRT-PCR based panel of MYC, MYCN, CCND1, CCND2, EGFR and FNDC3A was successful in detecting neoplasia with an overall accuracy of 54% in S-CRN compared to that of 29% in UC neoplastic samples. IHC study showed that p53 and CCND1 were significantly overexpressed with an increasing frequency from pre-neoplastic to neoplastic stages. EGFR and AMACR were expressed only in the neoplastic conditions.
CONCLUSION: CNVs that are common and unique to both UC-associated and sporadic colorectal neoplasm could be the key players driving carcinogenesis. Comparative analysis of CNVs provides testable driver aberrations but needs further evaluation in larger cohorts of samples. These markers may help in developing more effective neoplasia-detection strategies during screening and surveillance programs.

Abunimer AN, Salazar J, Noursi DP, Abu-Asab MS
A Systems Biology Interpretation of Array Comparative Genomic Hybridization (aCGH) Data through Phylogenetics.
OMICS. 2016; 20(3):169-79 [PubMed] Free Access to Full Article Related Publications
Array Comparative Genomic Hybridization (aCGH) is a rapid screening technique to detect gene deletions and duplications, providing an overview of chromosomal aberrations throughout the entire genome of a tumor, without the need for cell culturing. However, the heterogeneity of aCGH data obfuscates existing methods of data analysis. Analysis of aCGH data from a systems biology perspective or in the context of total aberrations is largely absent in the published literature. We present here a novel alternative to the functional analysis of aCGH data using the phylogenetic paradigm that is well-suited to high dimensional datasets of heterogeneous nature, but has not been widely adapted to aCGH data. Maximum parsimony phylogenetic analysis sorts out genetic data through the simplest presentation of the data on a cladogram, a graphical evolutionary tree, thus providing a powerful and efficient method for aCGH data analysis. For example, the cladogram models the multiphasic changes in the cancer genome and identifies shared early mutations in the disease progression, providing a simple yet powerful means of aCGH data interpretation. As such, applying maximum parsimony phylogenetic analysis to aCGH results allows for the differentiation between drivers and passenger genes aberrations in cancer specimens. In addition to offering a novel methodology to analyze aCGH results, we present here a crucial software suite that we wrote to carry out the analysis. In a broader context, we wish to underscore that phylogenetic analysis of aCGH data is a non-parametric method that circumvents the pitfalls and frustrations of standard analytical techniques that rely on parametric statistics. Organizing the data in a cladogram as explained in this research article provides insights into the disease common aberrations, as well as the disease subtypes and their shared aberrations (the synapomorphies) of each subtype. Hence, we report the method and make the software suite publicly and freely available at http://software.phylomcs.com so that researchers can test alternative and innovative approaches to the analysis of aCGH data.

Alvarez C, Aravena A, Tapia T, et al.
Different Array CGH profiles within hereditary breast cancer tumors associated to BRCA1 expression and overall survival.
BMC Cancer. 2016; 16:219 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. Moreover, specific genomic alterations may contribute to the identification of potential therapeutic targets and offer a more personalized treatment to breast cancer patients.
METHODS: Forty seven tumors from hereditary breast cancer cases, previously analyzed for BRCA1 expression, and screened for germline BRCA1 and 2 mutations, were analyzed by Array based Comparative Genomic Hybridization (aCGH) using Agilent 4x44K arrays. Overall survival was established for tumors in different clusters using Log-rank (Mantel-Cox) Test. Gene lists obtained from aCGH analysis were analyzed for Gene Ontology enrichment using GOrilla and DAVID tools.
RESULTS: Genomic profiling of the tumors showed specific alterations associated to BRCA1 or 2 mutation status, and BRCA1 expression in the tumors, affecting relevant cellular processes. Similar cellular functions were found affected in BRCA1 not expressing and BRCA1 or 2 mutated tumors. Hierarchical clustering classified hereditary breast tumors in four major, groups according to the type and amount of genomic alterations, showing one group with a significantly poor overall survival (p = 0.0221). Within this cluster, deletion of PLEKHO1, GDF11, DARC, DAG1 and CD63 may be associated to the worse outcome of the patients.
CONCLUSIONS: These results support the fact that BRCA1 lack of expression in tumors should be used as a marker for BRCAness and to select these patients for synthetic lethality approaches such as treatment with PARP inhibitors. In addition, the identification of specific alterations in breast tumors associated with poor survival, immune response or with a BRCAness phenotype will allow the use of a more personalized treatment in these patients.

Postel-Vinay S, Boursin Y, Massard C, et al.
Seeking the driver in tumours with apparent normal molecular profile on comparative genomic hybridization and targeted gene panel sequencing: what is the added value of whole exome sequencing?
Ann Oncol. 2016; 27(2):344-52 [PubMed] Related Publications
BACKGROUND: Molecular tumour profiling technologies have become increasingly important in the era of precision medicine, but their routine use is limited by their accessibility, cost, and tumour material availability. It is therefore crucial to assess their relative added value to optimize the sequence and combination of such technologies.
PATIENTS AND METHODS: Within the MOSCATO-01 trial, we investigated the added value of whole exome sequencing (WES) in patients that did not present any molecular abnormality on array comparative genomic hybridization (aCGH) and targeted gene panel sequencing (TGPS) using cancer specific panels. The pathogenicity potential and actionability of mutations detected on WES was assessed.
RESULTS: Among 420 patients enrolled between December 2011 and December 2013, 283 (67%) patients were analysed for both TGPS and aCGH. The tumour sample of 25 (8.8%) of them presented a flat (or low-dynamic) aCGH profile and no pathogenic mutation on TGPS. We selected the first eligible 10 samples-corresponding to a heterogeneous cohort of different tumour types-to perform WES. This allowed identifying eight mutations of interest in two patients: FGFR3, PDGFRB, and CREBBP missense single-nucleotide variants (SNVs) in an urothelial carcinoma; FGFR2, FBXW7, TP53, and MLH1 missense SNVs as well as an ATM frameshift mutation in a squamous cell carcinoma of the tongue. The FGFR3 alteration had been previously described as an actionable activating mutation and might have resulted in treatment by an FGFR inhibitor. CREBBP and ATM alterations might also have suggested a therapeutic orientation towards epigenetic modifiers and ataxia-telangectasia and Rad3-related inhibitors, respectively.
CONCLUSION: The therapeutic added value of performing WES on tumour samples that do not harbour any genetic abnormality on TGPS and aCGH might be limited and variable according to the histotype. Alternative techniques, including RNASeq and methylome analysis, might be more informative in selected cases.

Kjeldsen E
Oligo-based High-resolution aCGH Analysis Enhances Routine Cytogenetic Diagnostics in Haematological Malignancies.
Cancer Genomics Proteomics. 2015 Nov-Dec; 12(6):301-37 [PubMed] Related Publications
BACKGROUND: The purpose of the present study was to evaluate the detection rate of genomic aberrations in haematological malignancies using oligobased array-CGH (oaCGH) analysis in combination with karyotyping and fluorescence in situ hybridization (FISH) analyses, and its feasibility in a clinical pragmatic approach.
MATERIALS AND METHODS: The 4x180K Cancer Cytochip array was applied in 96 patients with various haematological malignancies in a prospective setting and in 41 acute myeloid leukemia (AML) patients retrospectively.
RESULTS: Combined use of oaCGH analysis and karyotyping improved the overall detection rate in comparison to karyotyping-alone and vice versa. In cases with normal karyotypes oaCGH analysis detected genomic aberrations in 66% (39/60) of cases. In the group of simple karyotypes oaCGH analysis extended karyotypic findings in 39% (12/31) while oaCGH analysis extended the karyotypic findings in 89% (39/44) of cases with complex karyotypes. In 7% (5/75) of cases oaCGH analysis failed in detecting the observed abnormalities by karyotyping.
CONCLUSION: oaCGH analysis is a valuable asset in routine cytogenetics of haematological malignancies.

Schroeder B, Shah N, Rostad S, et al.
Genetic investigation of multicentric glioblastoma multiforme: case report.
J Neurosurg. 2016; 124(5):1353-8 [PubMed] Related Publications
The authors report a case of multicentric glioblastoma multiforme (GBM) in which all 4 tumor foci were resected and evaluated using both comparative genomic hybridization array and RNA sequencing. Genetic analysis showed that the tumors shared a common origin, although each had its own unique set of genetic aberrations. The authors note that the genetic heterogeneity of multicentric GBM likely contributes to the failures of current treatments. The case underscores the necessity of increased genetic investigation.

Xu L, Zhang Y, Zhao H, et al.
Well-differentiated angiosarcoma of spleen: a teaching case mimicking hemagioma and cytogenetic analysis with array comparative genomic hybridization.
World J Surg Oncol. 2015; 13:300 [PubMed] Free Access to Full Article Related Publications
Primary splenic angiosarcoma is extremely rare but aggressive malignant vascular neoplasm. Here, we report a case of vascular tumor in spleen that was initially misinterpreted as hemangioma. Two years after splenectomy, the patient admitted again with aggravated abdomen pain and severe anemia. The magnetic resonance imaging (MRI) scan showed widely metastases. The ensuing biopsy for lesion both in liver and in bone marrow showed the similar pathological findings as that in spleen, which supported the final diagnosis of well-differentiated splenic angiosarcoma with extensive metastases. The patient was dead in 3 months after discharge without chemotherapy. The copy number changes for spleen lesion detected by array comparative genome hybridization showed copy number gain at 11q23.2, 11q24.3, 12q24.33, 13q34, copy number loss at 1q24.2-q31.3, 1q41-q42.2, 1 q42.3-q43, 2q36.3-q37.3, 2q37.7, 3q13.33-q26.2, 3q28 - q29, 9p11.2, 13q11, 15q11, homozygous copy loss at 8p11.22, 22q11.23. Less than 200 cases of splenic angiosarcoma have been published in literature of English. To the best of our knowledge, this is the first time analyzed cytogenetic alteration in a well-differentiated primary splenic angiosarcoma.

Li MM, Monzon FA, Biegel JA, et al.
A multicenter, cross-platform clinical validation study of cancer cytogenomic arrays.
Cancer Genet. 2015; 208(11):525-36 [PubMed] Related Publications
Cytogenomic microarray analysis (CMA) offers high resolution, genome-wide copy number information and is widely used in clinical laboratories for diagnosis of constitutional abnormalities. The Cancer Genomics Consortium (CGC) conducted a multiplatform, multicenter clinical validation project to compare the reliability and inter- and intralaboratory reproducibility of this technology for clinical oncology applications. Four specimen types were processed on three different microarray platforms-from Affymetrix, Agilent, and Illumina. Each microarray platform was employed at two independent test sites. The results were compared in a blinded manner with current standard methods, including karyotype, FISH, or morphology. Twenty-nine chronic lymphocytic leukemia blood, 34 myelodysplastic syndrome bone marrow, and 30 fresh frozen renal epithelial tumor samples were assessed by all six laboratories. Thirty formalin fixed paraffin embedded renal tumor samples were analyzed at the Affymetrix and Agilent test sites only. All study samples were initial diagnostic samples. Array data were analyzed at each participating site and were submitted to caArray for central analysis. Laboratory interpretive results were submitted to the central analysis team for comparison with the standard-of-care assays and for calculation of intraplatform reproducibility and cross-platform concordance. The results demonstrated that the three microarray platforms 1) detect clinically actionable genomic changes in cancer compatible to standard-of-care methods; 2) further define cytogenetic aberrations; 3) identify submicroscopic alterations and loss of heterozygosity (LOH); and 4) yield consistent results within and between laboratories. Based on this study, the CGC concludes that CMA is a sensitive and reliable technique for copy number and LOH assessment that may be used for clinical oncology genomic analysis.

Mühlbacher V, Haferlach T, Kern W, et al.
Array-based comparative genomic hybridization detects copy number variations with prognostic relevance in 80% of ALL with normal karyotype or failed chromosome analysis.
Leukemia. 2016; 30(2):318-24 [PubMed] Related Publications
Pretreatment cytogenetics is an important parameter for risk stratification and therapy approach in acute lymphoblastic leukemia (ALL). However, in up to 30% of cases, chromosome banding analysis (CBA) fails or reveals a normal karyotype. To characterize the subset of ALL with normal karyotype or failed CBA, we performed fluorescence in situ hybridization (FISH) or PCR for BCR-ABL1 and MLL rearrangements as well as array comparative genomic hybridization (aCGH) in 186 adult patients. We further carried out FISH for MYC in cases with Burkitt leukemia phenotype. FISH or PCR revealed one of the respective rearrangements in 22% of patients. In 80% of cases, copy number variations (CNV) were identified by aCGH. In 22% of cases, all CNV were below the resolution of CBA. On the basis of results of FISH, RT-PCR and aCGH, patients were categorized into three groups. The novel subset of patients with submicroscopic CNV only showed an overall survival at 3 years of 84% compared with 64% for patients classified as adverse abnormalities and 77% for cases with other aberrations (P=0.046). Thus, ALL with non-informative CBA can be further classified by FISH and aCGH providing prognostic information, which may be useful for a more individualized therapy.

Wu C, Pan J, Qiu H, et al.
Microarray CGH analysis of hematological patients with del(20q).
Int J Hematol. 2015; 102(5):617-25 [PubMed] Related Publications
Deletion of the long arm of chromosome 20 is a common abnormality underlying hematological malignancy. We analyzed 21 patients with hematologic diseases confirmed to carry the del(20q) by conventional cytogenetics and fluorescence in situ hybridization using microarray comparative genomic hybridization (aCGH). Seventeen patients were positive for del(20q), but this deletion was not detected in four patients. All deletions detected were interstitial of which continuous deletions were seen in 12 patients and discrete deletions in five. Three commonly deleted regions (CDRs) and two commonly retained regions (CRRs) were defined: CDR1 spanning 3.05Mb (34560497-37608229) within 20q11.23, CDR2 spanning 1.76Mb (37851501-39615698) within 20q12, CDR3 spanning 116Kb (48120412-48236791) within 20q13.13, CRR1 spanning 1.1Mb (29374726-30428250) within 20q11.21, and CRR2 spanning 2.5Mb (60484668-62963548) within 20q13.33. Duplications of retained regions (20q11.21) were found in five cases with similar erythroid hyperplasia (2 M6, 3 MDS). Moreover, duplication of 20p13-p11.21 was also found in two cases with M6. Using the CDRs and CRRs, we identified the candidate genes we searched for using the UCSC Genome Browser. Our data suggest that aCGH analysis is useful for more precisely defining breakpoints on 20q. Further work is required to identify candidate pathogenic genes within these CDRs and CRRs.

Song F, Li X, Song F, et al.
Comparative genomic analysis reveals bilateral breast cancers are genetically independent.
Oncotarget. 2015; 6(31):31820-9 [PubMed] Free Access to Full Article Related Publications
Bilateral breast cancer (BBC) poses a major challenge for oncologists because of the cryptic relationship between the two lesions. The purpose of this study was to determine the origin of the contralateral breast cancer (either dependent or independent of the index tumor). Here, we used ultra-deep whole-exome sequencing and array comparative genomic hybridization (aCGH) to study four paired samples of BBCs with different tumor subtypes and time intervals between the developments of each tumor. We used two paired primary breast tumors and corresponding metastatic liver lesions as the control. We tested the origin independent nature of BBC in three ways: mutational concordance, mutational signature clustering, and clonality analysis using copy number profiles. We found that the paired BBC samples had near-zero concordant mutation rates, which were much lower than those of the paired primary/metastasis samples. The results of a mutational signature analysis also suggested that BBCs are independent of one another. A clonality analysis using aCGH data further revealed that paired BBC samples was clonally independent, in contrast to clonal related origin found for paired primary/metastasis samples. Our preliminary findings show that BBCs in Han Chinese women are origin independent and thus should be treated separately.

Rack K, Vidrequin S, Dargent JL
Genomic profiling of myeloma: the best approach, a comparison of cytogenetics, FISH and array-CGH of 112 myeloma cases.
J Clin Pathol. 2016; 69(1):82-6 [PubMed] Related Publications
BACKGROUND: Chromosome abnormalities are important prognostic factors in myeloma allowing risk stratification of patients. Different techniques are available for their detection including cytogenetics, Fluorescent In Situ Hybridisation (FISH) and array Competitive Genomic Hybridisation (CGH). This study aimed to assess the validity and usefulness of each technique in a diagnostic setting.
METHODS: 112 myeloma cases were analysed by whole bone marrow cytogenetics and by FISH and array CGH performed on purified plasma cell populations.
RESULTS: Clonal abnormalities were identified in 30% of cases by cytogenetics and 97% by FISH and array CGH. By combining array and FISH results abnormalities were detected in 99% of cases and, if cytogenetic analysis was also considered, abnormalities were detected in 100% of cases.
CONCLUSIONS: Cytogenetic analysis is of limited value in myeloma. Array CGH and FISH are highly specific tests allowing the identification of aberrations in virtually all cases. The two techniques are complementary and need to be combined in order to provide a comprehensive analysis of all clinically relevant aberrations in myeloma.

Cabral de Almeida Cardoso L, Rodriguez-Laguna L, Del Carmen Crespo M, et al.
Array CGH Analysis of Paired Blood and Tumor Samples from Patients with Sporadic Wilms Tumor.
PLoS One. 2015; 10(8):e0136812 [PubMed] Free Access to Full Article Related Publications
Wilms tumor (WT), the most common cancer of the kidney in infants and children, has a complex etiology that is still poorly understood. Identification of genomic copy number variants (CNV) in tumor genomes provides a better understanding of cancer development which may be useful for diagnosis and therapeutic targets. In paired blood and tumor DNA samples from 14 patients with sporadic WT, analyzed by aCGH, 22% of chromosome abnormalities were novel. All constitutional alterations identified in blood were segmental (in 28.6% of patients) and were also present in the paired tumor samples. Two segmental gains (2p21 and 20q13.3) and one loss (19q13.31) present in blood had not been previously described in WT. We also describe, for the first time, a small, constitutive partial gain of 3p22.1 comprising 2 exons of CTNNB1, a gene associated to WT. Among somatic alterations, novel structural chromosomal abnormalities were found, like gain of 19p13.3 and 20p12.3, and losses of 2p16.1-p15, 4q32.5-q35.1, 4q35.2-q28.1 and 19p13.3. Candidate genes included in these regions might be constitutively (SIX3, SALL4) or somatically (NEK1, PIAS4, BMP2) operational in the development and progression of WT. To our knowledge this is the first report of CNV in paired blood and tumor samples in sporadic WT.

Beothe T, Zubakov D, Kovacs G
Homozygous losses detected by array comparative genomic hybridization in multiplex urothelial carcinomas of the bladder.
Cancer Genet. 2015; 208(9):434-40 [PubMed] Related Publications
Urothelial carcinomas (UCs) may present at first as a solitary or multifocal neoplasm. We applied high resolution array comparative genomic hybridization to 24 solitary and 32 multiplex UCs and used the hidden Markov model algorithm to identify the copy number changes at the probe level. Copy number losses and homozygous deletions at the chromosome 9p region affecting the CDKN2A and MTAP genes were the most frequent alterations in both groups of tumors. We have delineated two new tumor suppressor gene regions at chromosome 9p that harbor the PTPRD and BNC2 genes. Copy number losses at chromosomal regions 2q, 8p, and 18p occurred preferentially in solitary UCs, whereas multiplex UCs displayed loss of large chromosomal regions at 9q, 10q, 11q, 18q, and 21q. Homozygous deletions harboring loci of cell adhesion genes such as claudins, desmocollins, and desmogleins were seen exclusively in multiplex UCs. Amplifications occurred only in invasive G3 UCs irrespective of staging. Our study suggests that solitary and multiplex UCs may have divergent genetic pathways. The biallelic inactivation of cellular adhesion genes by homozygous deletions in multiplex UCs may explain the frequent intravesical spreading of tumor cells. .

Shao L, Miller S, Keller-Ramey J, et al.
Cytogenetic, fluorescence in situ hybridization, and genomic array characterization of chronic myeloid leukemia with cryptic BCR-ABL1 fusions.
Cancer Genet. 2015 Jul-Aug; 208(7-8):396-403 [PubMed] Related Publications
Chronic myeloid leukemia (CML) is characterized by the breakpoint cluster region (BCR)-Abelson murine leukemia (ABL1) fusion gene. In approximately 1% of CML cases, the Philadelphia chromosome associated with the BCR-ABL1 fusion gene is not present, and the BCR-ABL1 fusion gene is generated by cryptic insertion or sequential translocations. In this study, we describe the cytogenetic and molecular features of five CML patients with cryptic BCR-ABL1 fusion genes using karyotype, fluorescence in situ hybridization (FISH), and whole genome single nucleotide polymorphism array techniques. Two cases of CML in the chronic phase (CP) had a normal karyotype, and three cases of CML in the blast phase (BP) had an abnormal karyotype with neither a typical nor variant t(9;22). By BCR-ABL1 metaphase FISH analysis, we found that fusion signals were localized on chromosomes 9 (3 cases), 22 (1 case), and both 9 and 22 (1 case). In two cases of CML-BP, duplication of the BCR-ABL1 fusion gene occurred as a result of mitotic recombination between homologous chromosomes. Copy number losses involving the IKZF1 gene were observed in two patients with CML-BP. This study demonstrates for the first time the acquisition of additional BCR-ABL1 fusion genes through mitotic recombination in CML with cryptic BCR-ABL1.

Kanamori H, Kitamura Y, Kimura T, et al.
Genetic characterization of skull base chondrosarcomas.
J Neurosurg. 2015; 123(4):1036-41 [PubMed] Related Publications
OBJECT: Although chondrosarcomas rarely arise in the skull base, chondrosarcomas and chordomas are the 2 major malignant bone neoplasms occurring at this location. The distinction of these 2 tumors is important, but this distinction is occasionally problematic because of radiological and histological overlap. Unlike chordoma and extracranial chondrosarcoma, no case series presenting a whole-genome analysis of skull base chondrosarcomas (SBCSs) has been reported. The goal of this study is to clarify the genetic characteristics of SBCSs and contrast them with those of chordomas.
METHODS: The authors analyzed 7 SBCS specimens for chromosomal copy number alterations (CNAs) using comparative genomic hybridization (CGH). They also examined IDH1 and IDH2 mutations and brachyury expression.
RESULTS: In CGH analyses, the authors detected CNAs in 6 of the 7 cases, including chromosomal gains of 8q21.1, 19, 2q22-q32, 5qcen-q14, 8q21-q22, and 15qcen-q14. Mutation of IDH1 was found with a high frequency (5 of 7 cases, 71.4%), of which R132S was most frequently mutated. No IDH2 mutations were found, and immunohistochemical staining for brachyury was negative in all cases.
CONCLUSIONS: To the best of the authors' knowledge, this is the first whole-genome study of an SBSC case series. Their findings suggest that these tumors are molecularly consistent with a subset of conventional central chondrosarcomas and different from skull base chordomas.

Hammond DW, Al-Shammari NS, Danson S, et al.
High-Resolution Array CGH Analysis Identifies Regional Deletions and Amplifications of Chromosome 8 in Uveal Melanoma.
Invest Ophthalmol Vis Sci. 2015; 56(6):3460-6 [PubMed] Related Publications
PURPOSE: Monosomy 3 (M3) and abnormalities of chromosome 8 associate with poor prognosis in uveal melanomas (UM). Although M3 has been the subject of more in-depth studies, none have intensively focused on chromosome 8. To elucidate the potential role of chromosome 8 abnormalities, array comparative genomic hybridization (aCGH) was performed on primary UM.
METHODS: A specifically-designed custom high-resolution array was developed focusing on changes most implicated in UM. Probes for chromosome 8 had a mean spacing of 2.3 kb while chromosomes infrequently affected had a mean spacing of 36.6 kb. A series of 75 UM, including one formalin-fixed paraffin sample were analyzed, and where possible control DNA extracted from the patient's own peripheral blood was used.
RESULTS: The most common copy number abnormalities were chromosome 8 (75%) and M3 (51%), with M3 and gain of the long arm of chromosome 8 (8q+) associated in 41% of cases. Also identified were partial deletions of chromosome 3 (3%) and regional 8q+ (23%), and the intensive coverage of chromosome 8 revealed small focal deletions and amplifications affecting both arms. The most significant predictor of prognosis was M3/8q+ having a hazard ratio of 10.1 (P < 0.0001).
CONCLUSIONS: Neither 8p deletion nor focal changes affecting chromosome 8 were linked to outcome. The most significant indicator was M3/8q, and multiple 8q+ associated with shorter survival. Studying UM with this technology provides a powerful robust tool for predicting prognosis while considering other genetic changes, allowing the future incorporation of such data as it becomes clinically significant.

Arriba M, García JL, Inglada-Pérez L, et al.
DNA copy number profiling reveals different patterns of chromosomal instability within colorectal cancer according to the age of onset.
Mol Carcinog. 2016; 55(5):705-16 [PubMed] Related Publications
Chromosomal instability resulting in copy number alterations is a hallmark of colorectal cancer (CRC). However, few studies have attempted to characterize the chromosomal changes occurring in early-onset CRC in order to compare them with those taking place within the more extensively studied late-onset CRC subset. Our aim was to characterize the genomic profiles of these two groups of colorectal tumors and to compare them to each other. Array comparative genomic hybridization profiling of 146 colorectal tumors (60 early-onset and 86 late-onset) in combination with an unsupervised analysis was used to define common and specific copy number alterations. We found a number of important differences between the chromosomal instability profiles of each age subset. Thus, losses at 1p36, 1p12, 1q21, 9p13, 14q11, 16p13, and 16p12 were significantly more frequent in younger patients, whereas gains at 7q11 and 7q22 were more frequent in older patients. Moreover, the unsupervised analysis stratified the tumors into two clusters, each one of which was enriched in patients from one of the age subsets. Our findings confirm the existence of substantial differences between the chromosomal instability profiles of the two groups which are more important from a qualitative point of view. Further studies are needed to understand the clinicopathological implications of these dissimilarities.

Shapiro SG, Raghunath S, Williams C, et al.
Canine urothelial carcinoma: genomically aberrant and comparatively relevant.
Chromosome Res. 2015; 23(2):311-31 [PubMed] Free Access to Full Article Related Publications
Urothelial carcinoma (UC), also referred to as transitional cell carcinoma (TCC), is the most common bladder malignancy in both human and canine populations. In human UC, numerous studies have demonstrated the prevalence of chromosomal imbalances. Although the histopathology of the disease is similar in both species, studies evaluating the genomic profile of canine UC are lacking, limiting the discovery of key comparative molecular markers associated with driving UC pathogenesis. In the present study, we evaluated 31 primary canine UC biopsies by oligonucleotide array comparative genomic hybridization (oaCGH). Results highlighted the presence of three highly recurrent numerical aberrations: gain of dog chromosome (CFA) 13 and 36 and loss of CFA 19. Regional gains of CFA 13 and 36 were present in 97 % and 84 % of cases, respectively, and losses on CFA 19 were present in 77 % of cases. Fluorescence in situ hybridization (FISH), using targeted bacterial artificial chromosome (BAC) clones and custom Agilent SureFISH probes, was performed to detect and quantify these regions in paraffin-embedded biopsy sections and urine-derived urothelial cells. The data indicate that these three aberrations are potentially diagnostic of UC. Comparison of our canine oaCGH data with that of 285 human cases identified a series of shared copy number aberrations. Using an informatics approach to interrogate the frequency of copy number aberrations across both species, we identified those that had the highest joint probability of association with UC. The most significant joint region contained the gene PABPC1, which should be considered further for its role in UC progression. In addition, cross-species filtering of genome-wide copy number data highlighted several genes as high-profile candidates for further analysis, including CDKN2A, S100A8/9, and LRP1B. We propose that these common aberrations are indicative of an evolutionarily conserved mechanism of pathogenesis and harbor genes key to urothelial neoplasia, warranting investigation for diagnostic, prognostic, and therapeutic applications.

Yang XR, Killian JK, Hammond S, et al.
Characterization of genomic alterations in radiation-associated breast cancer among childhood cancer survivors, using comparative genomic hybridization (CGH) arrays.
PLoS One. 2015; 10(3):e0116078 [PubMed] Free Access to Full Article Related Publications
Ionizing radiation is an established risk factor for breast cancer. Epidemiologic studies of radiation-exposed cohorts have been primarily descriptive; molecular events responsible for the development of radiation-associated breast cancer have not been elucidated. In this study, we used array comparative genomic hybridization (array-CGH) to characterize genome-wide copy number changes in breast tumors collected in the Childhood Cancer Survivor Study (CCSS). Array-CGH data were obtained from 32 cases who developed a second primary breast cancer following chest irradiation at early ages for the treatment of their first cancers, mostly Hodgkin lymphoma. The majority of these cases developed breast cancer before age 45 (91%, n = 29), had invasive ductal tumors (81%, n = 26), estrogen receptor (ER)-positive staining (68%, n = 19 out of 28), and high proliferation as indicated by high Ki-67 staining (77%, n = 17 out of 22). Genomic regions with low-copy number gains and losses and high-level amplifications were similar to what has been reported in sporadic breast tumors, however, the frequency of amplifications of the 17q12 region containing human epidermal growth factor receptor 2 (HER2) was much higher among CCSS cases (38%, n = 12). Our findings suggest that second primary breast cancers in CCSS were enriched for an "amplifier" genomic subgroup with highly proliferative breast tumors. Future investigation in a larger irradiated cohort will be needed to confirm our findings.

Spina P, Coro I, De Donno A, et al.
Oligonucleotide Array-based Comparative Genomic Hybridization Approach in Hematologic Malignancies With Normal/Failed Conventional Cytogenetics and Fluorescent In Situ Hybridization.
Appl Immunohistochem Mol Morphol. 2016; 24(2):120-7 [PubMed] Related Publications
Oligonucleotide array-based comparative genomic hybridization (oaCGH) was used to investigate 60 cases of hematologic malignancies, mainly acute myeloid leukemias and myelodysplastic syndromes, in order to evaluate its sensitivity and specificity and to search for genomic alterations undetected by previous investigation with conventional cytogenetics (CC) and fluorescent in situ hybridization (FISH). On the basis of CC and FISH results, we subdivided the series into group A (36 cases with a normal karyotype after CC and/or FISH testing) and group B (24 cases with anomalies detected by CC and/or FISH). oaCGH did not show alterations in 21 cases of the group A (58.3%); in the remaining 15 cases (41.7%), it detected 19 new abnormalities (14 amplifications and 5 deletions). In the group B, oaCGH confirmed 32/55 aneuploidies detected by FISH (58.1%). The sensitivity increased at 27/33 confirmed aneuploidies (81.8%) by placing as a cutoff a mosaic of 50%. Moreover, in the cases of this group oaCGH revealed 36 new alterations (15 amplifications and 21 deletions). From these results it is possible to assess a strong overlap between results obtained by FISH and oaCGH. However, oaCGH is a reliable alternative where CC and FISH are not feasible and is able to identify new alterations unexplored by FISH.

Baughn LB, Biegel JA, South ST, et al.
Integration of cytogenomic data for furthering the characterization of pediatric B-cell acute lymphoblastic leukemia: a multi-institution, multi-platform microarray study.
Cancer Genet. 2015 Jan-Feb; 208(1-2):1-18 [PubMed] Related Publications
It is well documented that among subgroups of B-cell acute lymphoblastic leukemia (B-ALL), the genetic profile of the leukemic blasts has significant impact on prognosis and stratification for therapy. Recent studies have documented the power of microarrays to screen genome-wide for copy number aberrations (CNAs) and regions of copy number-neutral loss of heterozygosity (CNLOH) that are not detectable by G-banding or fluorescence in situ hybridization (FISH). These studies have involved application of a single array platform for the respective cases. The present investigation demonstrates the feasibility and usefulness of integrating array results from multiple laboratories (ARUP, The Children's Hospital of Philadelphia, Cincinnati Children's Hospital Medical Center, and University of Minnesota Medical Center) that utilize different array platforms (Affymetrix, Agilent, or Illumina) in their respective clinical settings. A total of 65 patients enrolled on the Children's Oncology Group (COG) study AALL08B1 were identified for study, as cytogenetic and FISH studies had also been performed on these patients, with a central review of those results available for comparison. Microarray data were first analyzed by the individual laboratories with their respective software systems; raw data files were then centrally validated using NEXUS software. The results demonstrated the added value of integrating multi-platform data with cytogenetic and FISH data and highlight novel findings identified by array including the co-occurrence of low and high risk abnormalities not previously reported to coexist within a clone, novel regions of chromosomal amplification, clones characterized by numerous whole chromosome LOH that do not meet criteria for doubling of a near-haploid, and characterization of array profiles associated with an IKZF1 deletion. Each of these findings raises questions that are clinically relevant to risk stratification.

Asai A, Karnan S, Ota A, et al.
High-resolution 400K oligonucleotide array comparative genomic hybridization analysis of neurofibromatosis type 1-associated cutaneous neurofibromas.
Gene. 2015; 558(2):220-6 [PubMed] Related Publications
Neurofibromatosis type 1 (NF1) is a genetic disorder where affected individuals develop benign or malignant nervous system tumors. To date, NF1 is caused by mutations in the NF1 tumor suppressor gene located at chromosome band 17q11.2. In this study, we aimed to characterize novel recurrent regional chromosomal imbalances and tumor-related candidate genes in NF1-associated cutaneous neurofibromas. Nine cutaneous neurofibromas from NF1 patients were screened for recurrent chromosomal imbalances using high-resolution 400K oligonucleotide array comparative genomic hybridization (aCGH). All the cases exhibited at least one sub-microscopic abnormality. Regions of recurrent chromosomal imbalances in a least one third of cases were loss of 1q13.2 (33%, FAM19A3), 1q21.1 (44%, RABGAP1L), 2q37.1 (56%, INPP5D), 3p25.1 (67%, CHCHD4), 4p15.32 (56%, FGFBP1), 5q11.2 (56%, ARL15), 6q22.31 (56%, NKAIN2), 6q22.33 (67%, ARHGAP18), 6q25.1 (67%, UST), 7q13 (56%, ADCY1), 12q13.13 (44%, KRT71), 19q13.32 (56%, GRLF1), and 20p11.21 (56%, NLP) and gain of 2p23.3 (76%, C2orf53), 8q22.3 (44%, ODF1) and 8q24.3 (67%, ARC). Several chromosomal imbalances, including loss of 7q11.23, 13q14.1, 14q32.13, 17p12, and 17q11.2 were detected at a lower frequency. We also confirmed that these chromosomal imbalances were not detected in the patient-matched lymphocyte DNAs. Amongst the 6 tumor-related candidate genes (RABGAP1L, ADCY1, SLIT2, GRLF1, UST, and ARC) identified in the regions of recurrent chromosomal imbalances, the gene expression changes of UST (down-regulation) and ARC (up-regulation) were found to be significantly associated with copy number alterations. The novel recurrent chromosomal imbalances and the altered expression levels of the tumor-related candidate genes may be associated with the development of NF1-associated benign cutaneous neurofibromas.

Lemée JM, Clavreul A, Aubry M, et al.
Characterizing the peritumoral brain zone in glioblastoma: a multidisciplinary analysis.
J Neurooncol. 2015; 122(1):53-61 [PubMed] Related Publications
Glioblastoma (GB) is the most frequent and aggressive type of primary brain tumor. Recurrences are mostly located at the margin of the resection cavity in the peritumoral brain zone (PBZ). Although it is widely believed that infiltrative tumor cells in this zone are responsible for GB recurrence, few studies have examined this zone. In this study, we analyzed PBZ left after surgery with a variety of techniques including radiology, histopathology, flow cytometry, genomic, transcriptomic, proteomic, and primary cell cultures. The resulting PBZ profiles were compared with those of the GB tumor zone and normal brain samples to identify characteristics specific to the PBZ. We found that tumor cell infiltration detected by standard histological analysis was present in almost one third of PBZ taken from an area that was considered normal both on standard MRI and by the neurosurgeon under an operating microscope. The panel of techniques used in this study show that the PBZ, similar to the tumor zone itself, is characterized by substantial inter-patient heterogeneity, which makes it difficult to identify representative markers. Nevertheless, we identified specific alterations in the PBZ such as the presence of selected tumor clones and stromal cells with tumorigenic and angiogenic properties. The study of GB-PBZ is a growing field of interest and this region needs to be characterized further. This will facilitate the development of new, targeted therapies for patients with GB and the development of approaches to refine the per-operative evaluation of the PBZ to optimize the surgical resection of the tumor.

Poorman K, Borst L, Moroff S, et al.
Comparative cytogenetic characterization of primary canine melanocytic lesions using array CGH and fluorescence in situ hybridization.
Chromosome Res. 2015; 23(2):171-86 [PubMed] Related Publications
Melanocytic lesions originating from the oral mucosa or cutaneous epithelium are common in the general dog population, with up to 100,000 diagnoses each year in the USA. Oral melanoma is the most frequent canine neoplasm of the oral cavity, exhibiting a highly aggressive course. Cutaneous melanocytomas occur frequently, but rarely develop into a malignant form. Despite the differential prognosis, it has been assumed that subtypes of melanocytic lesions represent the same disease. To address the relative paucity of information about their genomic status, molecular cytogenetic analysis was performed on the three recognized subtypes of canine melanocytic lesions. Using array comparative genomic hybridization (aCGH) analysis, highly aberrant distinct copy number status across the tumor genome for both of the malignant melanoma subtypes was revealed. The most frequent aberrations included gain of dog chromosome (CFA) 13 and 17 and loss of CFA 22. Melanocytomas possessed fewer genome wide aberrations, yet showed a recurrent gain of CFA 20q15.3-17. A distinctive copy number profile, evident only in oral melanomas, displayed a sigmoidal pattern of copy number loss followed immediately by a gain, around CFA 30q14. Moreover, when assessed by fluorescence in situ hybridization (FISH), copy number aberrations of targeted genes, such as gain of c-MYC (80 % of cases) and loss of CDKN2A (68 % of cases), were observed. This study suggests that in concordance with what is known for human melanomas, canine melanomas of the oral mucosa and cutaneous epithelium are discrete and initiated by different molecular pathways.

Liang JW, Shi ZZ, Shen TY, et al.
Identification of genomic alterations in pancreatic cancer using array-based comparative genomic hybridization.
PLoS One. 2014; 9(12):e114616 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genomic aberration is a common feature of human cancers and also is one of the basic mechanisms that lead to overexpression of oncogenes and underexpression of tumor suppressor genes. Our study aims to identify frequent genomic changes in pancreatic cancer.
MATERIALS AND METHODS: We used array comparative genomic hybridization (array CGH) to identify recurrent genomic alterations and validated the protein expression of selected genes by immunohistochemistry.
RESULTS: Sixteen gains and thirty-two losses occurred in more than 30% and 60% of the tumors, respectively. High-level amplifications at 7q21.3-q22.1 and 19q13.2 and homozygous deletions at 1p33-p32.3, 1p22.1, 1q22, 3q27.2, 6p22.3, 6p21.31, 12q13.2, 17p13.2, 17q21.31 and 22q13.1 were identified. Especially, amplification of AKT2 was detected in two carcinomas and homozygous deletion of CDKN2C in other two cases. In 15 independent validation samples, we found that AKT2 (19q13.2) and MCM7 (7q22.1) were amplified in 6 and 9 cases, and CAMTA2 (17p13.2) and PFN1 (17p13.2) were homozygously deleted in 3 and 1 cases. AKT2 and MCM7 were overexpressed, and CAMTA2 and PFN1 were underexpressed in pancreatic cancer tissues than in morphologically normal operative margin tissues. Both GISTIC and Genomic Workbench software identified 22q13.1 containing APOBEC3A and APOBEC3B as the only homozygous deletion region. And the expression levels of APOBEC3A and APOBEC3B were significantly lower in tumor tissues than in morphologically normal operative margin tissues. Further validation showed that overexpression of PSCA was significantly associated with lymph node metastasis, and overexpression of HMGA2 was significantly associated with invasive depth of pancreatic cancer.
CONCLUSION: These recurrent genomic changes may be useful for revealing the mechanism of pancreatic carcinogenesis and providing candidate biomarkers.

Aricò A, Ferraresso S, Bresolin S, et al.
Array-based comparative genomic hybridization analysis reveals chromosomal copy number aberrations associated with clinical outcome in canine diffuse large B-cell lymphoma.
PLoS One. 2014; 9(11):e111817 [PubMed] Free Access to Full Article Related Publications
Canine Diffuse Large B-cell Lymphoma (cDLBCL) is an aggressive cancer with variable clinical response. Despite recent attempts by gene expression profiling to identify the dog as a potential animal model for human DLBCL, this tumor remains biologically heterogeneous with no prognostic biomarkers to predict prognosis. The aim of this work was to identify copy number aberrations (CNAs) by high-resolution array comparative genomic hybridization (aCGH) in 12 dogs with newly diagnosed DLBCL. In a subset of these dogs, the genetic profiles at the end of therapy and at relapse were also assessed. In primary DLBCLs, 90 different genomic imbalances were counted, consisting of 46 gains and 44 losses. Two gains in chr13 were significantly correlated with clinical stage. In addition, specific regions of gains and losses were significantly associated to duration of remission. In primary DLBCLs, individual variability was found, however 14 recurrent CNAs (>30%) were identified. Losses involving IGK, IGL and IGH were always found, and gains along the length of chr13 and chr31 were often observed (>41%). In these segments, MYC, LDHB, HSF1, KIT and PDGFRα are annotated. At the end of therapy, dogs in remission showed four new CNAs, whereas three new CNAs were observed in dogs at relapse compared with the previous profiles. One ex novo CNA, involving TCR, was present in dogs in remission after therapy, possibly induced by the autologous vaccine. Overall, aCGH identified small CNAs associated with outcome, which, along with future expression studies, may reveal target genes relevant to cDLBCL.

Seabra AD, Araújo TM, Mello Junior FA, et al.
High-density array comparative genomic hybridization detects novel copy number alterations in gastric adenocarcinoma.
Anticancer Res. 2014; 34(11):6405-15 [PubMed] Related Publications
AIM: To investigate frequent quantitative alterations of intestinal-type gastric adenocarcinoma.
MATERIALS AND METHODS: We analyzed genome-wide DNA copy numbers of 22 samples and using CytoScan® HD Array.
RESULTS: We identified 22 gene alterations that to the best of our knowledge have not been described for gastric cancer, including of v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4 (ERBB4), SRY (sex determining region Y)-box 6 (SOX6), regulator of telomere elongation helicase 1 (RTEL1) and UDP-Gal:betaGlcNAc beta 1,4- galactosyltransferase, polypeptide 5 (B4GALT5). The most significant alterations related to peritoneal invasion involved the regions 13q21.1 (gain) and 15q15.1, 17q23.1, 19q13.2 and 20q11.22 (loss of heterozygozity; LOH), where we found LOH of erythrocyte membrane protein band 4.1-like 1 (EPB41L1) gene. In relation to early age of onset, the most significant alterations were gains in the regions Xq26 and Xp22.31 and a loss in the region 11p15.4.
CONCLUSION: These quantitative changes may play a role in the development of this type of neoplasia and may be used as markers in evaluating poor prognosis, as well as act as potential therapeutic targets for gastric cancer.

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