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Publication Record


Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats.
Stankiewicz P, Kulkarni S, Dharmadhikari AV, Sampath S, Bhatt SS, Shaikh TH, Xia Z, Pursley AN, Cooper ML, Shinawi M, Paciorkowski AR, Grange DK, Noetzel MJ, Saunders S, Simons P, Summar M, Lee B, Scaglia F, Fellmann F, Martinet D, Beckmann JS, Asamoah A, Platky K, Sparks S, Martin AS, Madan-Khetarpal S, Hoover J, Medne L, Bonnemann CG, Moeschler JB, Vallee SE, Parikh S, Irwin P, Dalzell VP, Smith WE, Banks VC, Flannery DB, Lovell CM, Bellus GA, Golden-Grant K, Gorski JL, Kussmann JL, McGregor TL, Hamid R, Pfotenhauer J, Ballif BC, Shaw CA, Kang SH, Bacino CA, Patel A, Rosenfeld JA, Cheung SW, Shaffer LG
(2012) Hum Mutat 33: 165-79
MeSH Terms: Abnormalities, Multiple, Child, Child, Preschool, Chromosome Aberrations, Chromosome Mapping, Chromosomes, Human, Pair 10, DNA Copy Number Variations, Developmental Disabilities, Female, Genetic Variation, Homologous Recombination, Humans, In Situ Hybridization, Fluorescence, Infant, Intellectual Disability, Male, Nerve Growth Factors, Oligonucleotide Array Sequence Analysis, Penetrance, Segmental Duplications, Genomic, Sequence Deletion, Vesicular Acetylcholine Transport Proteins
Show Abstract · Added March 27, 2014
We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.
© 2011 Wiley Periodicals, Inc.
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22 MeSH Terms
Factors that impact susceptibility to fiber-induced health effects.
Below JE, Cox NJ, Fukagawa NK, Hirvonen A, Testa JR
(2011) J Toxicol Environ Health B Crit Rev 14: 246-66
MeSH Terms: Age Factors, Animals, Asbestos, Carcinogens, Environmental, Chromosome Aberrations, Cocarcinogenesis, Disease Susceptibility, Environmental Pollutants, Genetic Predisposition to Disease, Humans, Mesothelioma, Mineral Fibers, Nutritional Status, Radiation Effects, Risk, Sex Characteristics, Zeolites
Show Abstract · Added February 22, 2016
Asbestos and related fibers are associated with a number of adverse health effects, including malignant mesothelioma (MM), an aggressive cancer that generally develops in the surface serosal cells of the pleural, pericardial, and peritoneal cavities. Although approximately 80% of individuals with MM are exposed to asbestos, fewer than 5% of asbestos workers develop MM. In addition to asbestos, other mineralogical, environmental, genetic, and possibly viral factors might contribute to MM susceptibility. Given this complex etiology of MM, understanding susceptibility to MM needs to be a priority for investigators in order to reduce exposure of those most at risk to known environmental carcinogens. In this review, the current body of literature related to fiber-associated disease susceptibility including age, sex, nutrition, genetics, asbestos, and other mineral exposure is addressed with a focus on MM, and critical areas for further study are recommended.
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17 MeSH Terms
Molecular profiling of cancer--the future of personalized cancer medicine: a primer on cancer biology and the tools necessary to bring molecular testing to the clinic.
Stricker T, Catenacci DV, Seiwert TY
(2011) Semin Oncol 38: 173-85
MeSH Terms: Chromosome Aberrations, Clinical Trials as Topic, Comparative Genomic Hybridization, DNA Methylation, DNA Repair, Gene Fusion, Humans, Mutation, Neoplasms, Oncogenes, Precision Medicine, Systems Biology
Show Abstract · Added March 28, 2014
Cancers arise as a result of an accumulation of genetic aberrations that are either acquired or inborn. Virtually every cancer has its unique set of molecular changes. Technologies have been developed to study cancers and derive molecular characteristics that increasingly have implications for clinical care. Indeed, the identification of key genetic aberrations (molecular drivers) may ultimately translate into dramatic benefit for patients through the development of highly targeted therapies. With the increasing availability of newer, more powerful, and cheaper technologies such as multiplex mutational screening, next generation sequencing, array-based approaches that can determine gene copy numbers, methylation, expression, and others, as well as more sophisticated interpretation of high-throughput molecular information using bioinformatics tools like signatures and predictive algorithms, cancers will routinely be characterized in the near future. This review examines the background information and technologies that clinicians and physician-scientists will need to interpret in order to develop better, personalized treatment strategies.
Copyright © 2011 Elsevier Inc. All rights reserved.
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12 MeSH Terms
Copy number variations and clinical outcome in atypical spitz tumors.
Raskin L, Ludgate M, Iyer RK, Ackley TE, Bradford CR, Johnson TM, Fullen DR
(2011) Am J Surg Pathol 35: 243-52
MeSH Terms: Adolescent, Adult, Aged, Child, Child, Preschool, Chromosome Aberrations, Comparative Genomic Hybridization, DNA, Neoplasm, Female, Gene Dosage, Humans, In Situ Hybridization, Fluorescence, Male, Melanoma, Middle Aged, Nevus, Epithelioid and Spindle Cell, Skin Neoplasms, Young Adult
Show Abstract · Added March 5, 2014
Atypical Spitz tumors (ASTs) are rare spitzoid neoplasms of uncertain biological behavior. Our study was designed to characterize genetic abnormalities that may help to differentiate ASTs from melanoma or Spitz nevi. We examined copy number variation in formalin-fixed, paraffin-embedded samples using an Agilent 44k array comparative genomic hybridization platform. Sixteen patients with AST (8 with positive sentinel lymph node biopsy, 1 with distant metastasis), 8 patients with Spitz nevi, and 3 patients with melanoma (2 spitzoid, 1 superficial spreading) were evaluated. Chromosomal aberrations were found in 7 of 16 ASTs, 1 with fatal outcome, 2 spitzoid melanomas, and 1 conventional melanoma. We found no difference in chromosomal instability between AST patients with positive and negative sentinel lymph node biopsies. Our patient with widely metastatic AST lacked the most frequent aberrations in melanoma involving chromosomes 6 and 11q that are loci targeted by fluorescence in situ hybridization (FISH) probes developed to distinguish malignant melanoma from benign melanocytic lesions. The vast majority of chromosomal abnormalities observed in ASTs are not commonly found in melanomas, suggesting that AST may be a distinct clinical entity and raising additional questions regarding their malignant potential, prognosis, and clinical management. The current FISH probes failed to detect 1 spitzoid melanoma, 1 fatal metastatic AST case, and the other chromosomally aberrant ASTs in our series, but detected 1 spitzoid melanoma and 1 conventional melanoma. Thus, a comprehensive, genome-wide approach to chromosomal abnormalities offered greater sensitivity and specificity than current FISH probes in identifying spitzoid lesions of uncertain malignant potential in this series.
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18 MeSH Terms
Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension.
Aldred MA, Comhair SA, Varella-Garcia M, Asosingh K, Xu W, Noon GP, Thistlethwaite PA, Tuder RM, Erzurum SC, Geraci MW, Coldren CD
(2010) Am J Respir Crit Care Med 182: 1153-60
MeSH Terms: Adult, Airway Remodeling, Bone Morphogenetic Protein Receptors, Type II, Cell Proliferation, Child, Chromosome Aberrations, Chromosome Deletion, DNA Copy Number Variations, Endothelial Cells, Female, Gene Rearrangement, Genome-Wide Association Study, Genomic Instability, Germ-Line Mutation, Humans, Hypertension, Pulmonary, In Situ Hybridization, Fluorescence, Lung, Microarray Analysis, Middle Aged, Myocytes, Smooth Muscle, Polymorphism, Single Nucleotide, Pulmonary Artery, Pulmonary Disease, Chronic Obstructive, X Chromosome Inactivation
Show Abstract · Added November 17, 2011
RATIONALE - Vascular remodeling in pulmonary arterial hypertension (PAH) involves proliferation and migration of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Previous studies have indicated that the endothelial cell proliferation is quasineoplastic, with evidence of monoclonality and instability of short DNA microsatellite sequences.
OBJECTIVES - To assess whether there is larger-scale genomic instability.
METHODS - We performed genome-wide microarray copy number analysis on pulmonary artery endothelial cells and smooth muscle cells isolated from the lungs of patients with PAH.
MEASUREMENTS AND MAIN RESULTS - Mosaic chromosomal abnormalities were detected in PAEC cultures from five of nine PAH lungs but not in normal (n = 8) or disease control subjects (n = 5). Fluorescent in situ hybridization analysis confirmed the presence of these abnormalities in vivo in two of three cases. One patient harbored a germline mutation of BMPR2, the primary genetic cause of PAH, and somatic loss of chromosome-13, which constitutes a second hit in the same pathway by deleting Smad-8. In two female subjects with mosaic loss of the X chromosome, methylation analysis showed that the active X was deleted. One subject also showed completely skewed X-inactivation in the nondeleted cells, suggesting the pulmonary artery endothelial cell population was clonal before the acquisition of the chromosome abnormality.
CONCLUSIONS - Our data indicate a high frequency of genetically abnormal subclones within PAH lung vessels and provide the first definitive evidence of a second genetic hit in a patient with a germline BMPR2 mutation. We propose that these chromosome abnormalities may confer a growth advantage and thus contribute to the progression of PAH.
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25 MeSH Terms
Kinase expression and chromosomal rearrangements in papillary thyroid cancer tissues: investigations at the molecular and microscopic levels.
Weier HU, Kwan J, Lu CM, Ito Y, Wang M, Baumgartner A, Hayward SW, Weier JF, Zitzelsberger HF
(2009) J Physiol Pharmacol 60 Suppl 4: 47-55
MeSH Terms: Animals, Carcinoma, Papillary, Cell Line, Cell Transplantation, Chernobyl Nuclear Accident, Chromosome Aberrations, Chromosomes, Chromosomes, Artificial, Bacterial, Cloning, Molecular, DNA Probes, Flow Cytometry, Humans, Image Processing, Computer-Assisted, Karyotyping, Mice, Protein Kinases, Receptor Protein-Tyrosine Kinases, Receptor, trkA, Reverse Transcriptase Polymerase Chain Reaction, Thyroid Neoplasms, Translocation, Genetic
Show Abstract · Added May 27, 2014
Structural chromosome aberrations are known hallmarks of many solid tumors. In the papillary form of thyroid cancer (PTC), for example, activation of the receptor tyrosine kinase (RTK) genes, ret or the neurotrophic tyrosine kinase receptor type I (NTRK1) by intra- or interchromosomal rearrangements have been suggested as a cause of the disease. The 1986 accident at the nuclear power plant in Chernobyl, Ukraine, led to the uncontrolled release of high levels of radioisotopes. Ten years later, the incidence of childhood papillary thyroid cancer (chPTC) near Chernobyl had risen by two orders of magnitude. Tumors removed from some of these patients showed aberrant expression of the ret RTK gene due to a ret/PTC1 or ret/PTC3 rearrangement involving chromosome 10. However, many cultured chPTC cells show a normal G-banded karyotype and no ret rearrangement. We hypothesize that the "ret-negative" tumors inappropriately express a different oncogene or have lost function of a tumor suppressor as a result of chromosomal rearrangements, and decided to apply molecular and cytogenetic methods to search for potentially oncogenic chromosomal rearrangements in Chernobyl chPTC cases. Knowledge of the kind of genetic alterations may facilitate the early detection and staging of chPTC as well as provide guidance for therapeutic intervention.
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21 MeSH Terms
An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors.
Chitale D, Gong Y, Taylor BS, Broderick S, Brennan C, Somwar R, Golas B, Wang L, Motoi N, Szoke J, Reinersman JM, Major J, Sander C, Seshan VE, Zakowski MF, Rusch V, Pao W, Gerald W, Ladanyi M
(2009) Oncogene 28: 2773-83
MeSH Terms: Adenocarcinoma, Cell Line, Tumor, Cell Proliferation, Chromosome Aberrations, Cluster Analysis, Cyclin-Dependent Kinase Inhibitor p16, Dual-Specificity Phosphatases, ErbB Receptors, Female, Gene Dosage, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, ras, Genome-Wide Association Study, Humans, In Situ Hybridization, Fluorescence, Kaplan-Meier Estimate, Lung Neoplasms, Male, Mitogen-Activated Protein Kinase Phosphatases, Mutation, Nucleic Acid Hybridization, RNA Interference
Show Abstract · Added March 24, 2014
To address the biological heterogeneity of lung cancer, we studied 199 lung adenocarcinomas by integrating genome-wide data on copy number alterations and gene expression with full annotation for major known somatic mutations in this cancer. This showed non-random patterns of copy number alterations significantly linked to EGFR and KRAS mutation status and to distinct clinical outcomes, and led to the discovery of a striking association of EGFR mutations with underexpression of DUSP4, a gene within a broad region of frequent single-copy loss on 8p. DUSP4 is involved in negative feedback control of EGFR signaling, and we provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. DUSP4 loss also associates with p16/CDKN2A deletion and defines a distinct clinical subset of lung cancer patients. Another novel observation is that of a reciprocal relationship between EGFR and LKB1 mutations. These results highlight the power of integrated genomics to identify candidate driver genes within recurrent broad regions of copy number alteration and to delineate distinct oncogenetic pathways in genetically complex common epithelial cancers.
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23 MeSH Terms
PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR.
Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R, Zander T, Seeger JM, Weiss J, Fischer F, Frommolt P, Michel K, Peifer M, Mermel C, Girard L, Peyton M, Gazdar AF, Minna JD, Garraway LA, Kashkar H, Pao W, Meyerson M, Thomas RK
(2009) Cancer Res 69: 3256-61
MeSH Terms: Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Chromosome Aberrations, Cluster Analysis, Drug Resistance, Neoplasm, Enzyme Activation, ErbB Receptors, Erlotinib Hydrochloride, Gene Deletion, Gene Expression, Humans, Lung Neoplasms, PTEN Phosphohydrolase, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Quinazolines
Show Abstract · Added March 24, 2014
Clinical resistance to epidermal growth factor receptor (EGFR) inhibition in lung cancer has been linked to the emergence of the EGFR T790M resistance mutation or amplification of MET. Additional mechanisms contributing to EGFR inhibitor resistance remain elusive. By applying combined analyses of gene expression, copy number, and biochemical analyses of EGFR inhibitor responsiveness, we identified homozygous loss of PTEN to segregate EGFR-dependent and EGFR-independent cells. We show that in EGFR-dependent cells, PTEN loss partially uncouples mutant EGFR from downstream signaling and activates EGFR, thereby contributing to erlotinib resistance. The clinical relevance of our findings is supported by the observation of PTEN loss in 1 out of 24 primary EGFR-mutant non-small cell lung cancer (NSCLC) tumors. These results suggest a novel resistance mechanism in EGFR-mutant NSCLC involving PTEN loss.
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16 MeSH Terms
DNA aneuploidy study for early detection of chromosomal abnormality in patients with aplastic anemia: prognostic and therapeutic implications.
Tripathi P, Tripathi AK, Kumar A, Ahmad R, Balapure AK, Vishwakerma AL, Singh RK
(2008) In Vivo 22: 837-44
MeSH Terms: Adolescent, Adult, Anemia, Aplastic, Aneuploidy, Chromosome Aberrations, DNA, Female, Flow Cytometry, Humans, Immunosuppressive Agents, Male, Middle Aged, Prognosis, Software, Young Adult
Show Abstract · Added July 12, 2013
BACKGROUND - Undetected aneuploidy exists in a large percentage of patients with aplastic anemia at the time of diagnosis, which may not be identified by conventional cytogenetics. The presence of aneuploidy at any time in the clinical course implies poor prognosis in such patients. This warrants a need for the early detection of chromosomal abnormalities for prognosis and delineation of therapeutic modalities.
PATIENTS AND METHODS - Fifty patients with aplastic anemia and 30 controls were studied with an aim to determine the role of aneuploidy as an indicator of chromosomal abnormalities. DNA aneuploidy analysis was carried out by flow cytometry using Mod Fit-LT V3.0 software, whereas chromosomal analysis was performed by conventional cytogenetics.
RESULTS - DNA aneuploidy was present in 14% of cases and chromosomal abnormalities were found in 4% of cases of aplastic anemia at the time of diagnosis before therapy. Overall, DNA aneuploidy was detected in 36% of cases by flow cytometry, whereas the cytogenetic method revealed chromosomal abnormalities in 14% of cases of aplastic anemia. Flow cytometric analysis showed hypodiploidy in one patient at the time of diagnosis who developed monosomy 7 during follow-up. All patients with hypodiploidy had short survival and they did not respond to therapy.
CONCLUSION - The present study demonstrates the role of flow cytometry in the early detection of chromosomal abnormalities in patients at a time when they remain undetected by conventional cytogenetics. The presence of DNA aneuploidy in patients with aplastic anemia may be an early indicator of subsequent overt cytogenetic abnormality, associated with poor response to immunosuppressive therapy and a lower survival.
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15 MeSH Terms
Histone deacetylase inhibitor romidepsin has differential activity in core binding factor acute myeloid leukemia.
Odenike OM, Alkan S, Sher D, Godwin JE, Huo D, Brandt SJ, Green M, Xie J, Zhang Y, Vesole DH, Stiff P, Wright J, Larson RA, Stock W
(2008) Clin Cancer Res 14: 7095-101
MeSH Terms: Antibiotics, Antineoplastic, Chromosome Aberrations, Cohort Studies, Core Binding Factors, Depsipeptides, Drug Evaluation, Enzyme Inhibitors, Female, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Leukemia, Myeloid, Acute, Male, Middle Aged
Show Abstract · Added March 19, 2014
PURPOSE - Recruitment of histone deacetylases (HDAC) is a mechanism of transcriptional repression implicated in the differentiation block in acute myeloid leukemia (AML). We hypothesized that the HDAC inhibitor romidepsin could cause transcriptional derepression, up-regulation of specific target genes in AML, and differentiation of the leukemic clone. The primary objectives of the study were to evaluate the safety and efficacy of romidepsin in advanced AML.
EXPERIMENTAL DESIGN - Twenty patients were stratified into cohort A or B based on the absence or presence of chromosomal abnormalities known to recruit HDACs, including those involving core binding factor (CBF). Romidepsin was administered i.v. at 13 mg/m(2)/d on days 1, 8, and 15 of a 28-day cycle. Pharmacodynamic endpoints were evaluated at serial time points.
RESULTS - Common adverse effects noted were grade 1 to 2 nausea, anorexia, and fatigue. No objective evidence of antileukemic activity was seen in cohort A. In cohort B, although there were no clinical responses by standard criteria, antileukemic activity was observed in 5 of 7 patients. Two patients had clearance of bone marrow blasts and 3 patients had a >50% decrease in bone marrow blasts. Furthermore, in cohort B, at 24 h, there was a significant increase in MDR1 (P=0.005), p15 (P=0.01), and p14 (P<0.0001) expression. In cohort A, although there was a trend toward up-regulation of MDR1, p15, and p14 expression, these changes were not statistically significant.
CONCLUSION - Romidepsin has differential antileukemic and molecular activity in CBF AML. Development of this agent in CBF AML should focus on combinations that target related mechanisms of gene silencing such as DNA methylation.
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14 MeSH Terms