35 results on '"Lennon PA"'
Search Results
2. Immunohistochemical profile and fluorescence in situ hybridization analysis of diffuse large B-cell lymphoma in northern China.
- Author
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Li T, Medeiros LJ, Lin P, Yin H, Littlejohn M, Im W, Lennon PA, Hu P, Jorgensen JL, Liang M, Guo H, and Yin CC
- Published
- 2010
- Full Text
- View/download PDF
3. Optical genome mapping in acute myeloid leukemia: a multicenter evaluation.
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Levy B, Baughn LB, Akkari Y, Chartrand S, LaBarge B, Claxton D, Lennon PA, Cujar C, Kolhe R, Kroeger K, Pitel B, Sahajpal N, Sathanoori M, Vlad G, Zhang L, Fang M, Kanagal-Shamanna R, and Broach JR
- Subjects
- Humans, In Situ Hybridization, Fluorescence, Karyotype, Chromosome Mapping, Chromosome Aberrations, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics
- Abstract
Detection of hallmark genomic aberrations in acute myeloid leukemia (AML) is essential for diagnostic subtyping, prognosis, and patient management. However, cytogenetic/cytogenomic techniques used to identify those aberrations, such as karyotyping, fluorescence in situ hybridization (FISH), or chromosomal microarray analysis (CMA), are limited by the need for skilled personnel as well as significant time, cost, and labor. Optical genome mapping (OGM) provides a single, cost-effective assay with a significantly higher resolution than karyotyping and with a comprehensive genome-wide analysis comparable with CMA and the added unique ability to detect balanced structural variants (SVs). Here, we report in a real-world setting the performance of OGM in a cohort of 100 AML cases that were previously characterized by karyotype alone or karyotype and FISH or CMA. OGM identified all clinically relevant SVs and copy number variants (CNVs) reported by these standard cytogenetic methods when representative clones were present in >5% allelic fraction. Importantly, OGM identified clinically relevant information in 13% of cases that had been missed by the routine methods. Three cases reported with normal karyotypes were shown to have cryptic translocations involving gene fusions. In 4% of cases, OGM findings would have altered recommended clinical management, and in an additional 8% of cases, OGM would have rendered the cases potentially eligible for clinical trials. The results from this multi-institutional study indicate that OGM effectively recovers clinically relevant SVs and CNVs found by standard-of-care methods and reveals additional SVs that are not reported. Furthermore, OGM minimizes the need for labor-intensive multiple cytogenetic tests while concomitantly maximizing diagnostic detection through a standardized workflow., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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4. Assessing copy number abnormalities and copy-neutral loss-of-heterozygosity across the genome as best practice in diagnostic evaluation of acute myeloid leukemia: An evidence-based review from the cancer genomics consortium (CGC) myeloid neoplasms working group.
- Author
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Xu X, Bryke C, Sukhanova M, Huxley E, Dash DP, Dixon-Mciver A, Fang M, Griepp PT, Hodge JC, Iqbal A, Jeffries S, Kanagal-Shamanna R, Quintero-Rivera F, Shetty S, Slovak ML, Yenamandra A, Lennon PA, and Raca G
- Subjects
- Humans, DNA Copy Number Variations, Evidence-Based Medicine, Leukemia, Myeloid, Acute genetics, Loss of Heterozygosity
- Abstract
Structural genomic abnormalities, including balanced chromosomal rearrangements, copy number gains and losses and copy-neutral loss-of-heterozygosity (CN-LOH) represent an important category of diagnostic, prognostic and therapeutic markers in acute myeloid leukemia (AML). Genome-wide evaluation for copy number abnormalities (CNAs) is at present performed by karyotype analysis which has low resolution and is unobtainable in a subset of cases. Furthermore, examination for possible CN-LOH in leukemia cells is at present not routinely performed in the clinical setting. Chromosomal microarray (CMA) analysis is a widely available assay for CNAs and CN-LOH in diagnostic laboratories, but there are currently no guidelines how to best incorporate this technology into clinical testing algorithms for neoplastic diseases including AML. The Cancer Genomics Consortium Working Group for Myeloid Neoplasms performed an extensive review of peer-reviewed publications focused on CMA analysis in AML. Here we summarize evidence regarding clinical utility of CMA analysis in AML extracted from published data, and provide recommendations for optimal utilization of CMA testing in the diagnostic workup. In addition, we provide a list of CNAs and CN-LOH regions which have documented clinical significance in diagnosis, prognosis and treatment decisions in AML., (Copyright © 2018. Published by Elsevier Inc.)
- Published
- 2018
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5. Assessing copy number aberrations and copy neutral loss of heterozygosity across the genome as best practice: An evidence based review of clinical utility from the cancer genomics consortium (CGC) working group for myelodysplastic syndrome, myelodysplastic/myeloproliferative and myeloproliferative neoplasms.
- Author
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Kanagal-Shamanna R, Hodge JC, Tucker T, Shetty S, Yenamandra A, Dixon-McIver A, Bryke C, Huxley E, Lennon PA, Raca G, Xu X, Jeffries S, Quintero-Rivera F, Greipp PT, Slovak ML, Iqbal MA, and Fang M
- Subjects
- Humans, DNA Copy Number Variations, Loss of Heterozygosity, Myelodysplastic Syndromes genetics, Myeloproliferative Disorders genetics
- Abstract
Multiple studies have demonstrated the utility of chromosomal microarray (CMA) testing to identify clinically significant copy number alterations (CNAs) and copy-neutral loss-of-heterozygosity (CN-LOH) in myeloid malignancies. However, guidelines for integrating CMA as a standard practice for diagnostic evaluation, assessment of prognosis and predicting treatment response are still lacking. CMA has not been recommended for clinical work-up of myeloid malignancies by the WHO 2016 or the NCCN 2017 guidelines but is a suggested test by the European LeukaemiaNet 2013 for the diagnosis of primary myelodysplastic syndrome (MDS). The Cancer Genomics Consortium (CGC) Working Group for Myeloid Neoplasms systematically reviewed peer-reviewed literature to determine the power of CMA in (1) improving diagnostic yield, (2) refining risk stratification, and (3) providing additional genomic information to guide therapy. In this manuscript, we summarize the evidence base for the clinical utility of array testing in the workup of MDS, myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and myeloproliferative neoplasms (MPN). This review provides a list of recurrent CNAs and CN-LOH noted in this disease spectrum and describes the clinical significance of the aberrations and how they complement gene mutation findings by sequencing. Furthermore, for new or suspected diagnosis of MDS or MPN, we present suggestions for integrating genomic testing methods (CMA and mutation testing by next generation sequencing) into the current standard-of-care clinical laboratory testing (karyotype, FISH, morphology, and flow)., (Copyright © 2018. Published by Elsevier Inc.)
- Published
- 2018
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6. Addition of chromosomal microarray and next generation sequencing to FISH and classical cytogenetics enhances genomic profiling of myeloid malignancies.
- Author
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Mukherjee S, Sathanoori M, Ma Z, Andreatta M, Lennon PA, Wheeler SR, Prescott JL, Coldren C, Casey T, Rietz H, Fasig K, Woodford R, Hartley T, Spence D, Donnelan W, Berdeja J, Flinn I, Kozyr N, Bouzyk M, Correll M, Ho H, Kravtsov V, Tunnel D, and Chandra P
- Subjects
- Cohort Studies, DNA Copy Number Variations genetics, Humans, Mutation genetics, Myeloproliferative Disorders diagnosis, Tumor Burden, Chromosomes, Human genetics, Cytogenetics methods, Genomics methods, High-Throughput Nucleotide Sequencing methods, In Situ Hybridization, Fluorescence methods, Myeloproliferative Disorders genetics, Oligonucleotide Array Sequence Analysis methods
- Abstract
Comprehensive genetic profiling is increasingly important for the clinical workup of hematologic tumors, as specific alterations are now linked to diagnostic characterization, prognostic stratification and therapy selection. To characterize relevant genetic and genomic alterations in myeloid malignancies maximally, we utilized a comprehensive strategy spanning fluorescence in situ hybridization (FISH), classical karyotyping, Chromosomal Microarray (CMA) for detection of copy number variants (CNVs) and Next generation Sequencing (NGS) analysis. In our cohort of 569 patients spanning the myeloid spectrum, NGS and CMA testing frequently identified mutations and copy number changes in the majority of genes with important clinical associations, such as TP53, TET2, RUNX1, SRSF2, APC and ATM. Most importantly, NGS and CMA uncovered medically actionable aberrations in 75.6% of cases normal by FISH/cytogenetics testing. NGS identified mutations in 65.5% of samples normal by CMA, cytogenetics and FISH, whereas CNVs were detected in 10.1% cases that were normal by all other methodologies. Finally, FISH or cytogenetics, or both, were abnormal in 14.1% of cases where NGS or CMA failed to detect any changes. Multiple mutations and CNVs were found to coexist, with potential implications for patient stratification. Thus, high throughput genomic tumor profiling through targeted DNA sequencing and CNV analysis complements conventional methods and leads to more frequent detection of actionable alterations., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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7. Chromosomal microarray provides enhanced targetable gene aberration detection when paired with next generation sequencing panel in profiling lung and colorectal tumors.
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Mukherjee S, Ma Z, Wheeler S, Sathanoori M, Coldren C, Prescott JL, Kozyr N, Bouzyk M, Correll M, Ho H, Chandra PK, and Lennon PA
- Subjects
- Chromosome Aberrations, Cohort Studies, High-Throughput Nucleotide Sequencing methods, Humans, Loss of Heterozygosity, Male, Tissue Array Analysis methods, Colorectal Neoplasms genetics, Lung Neoplasms genetics, Transcriptional Activation genetics
- Abstract
The development of targeted therapies based on specific genomic alterations has altered the treatment and management of lung and colorectal cancers. Chromosomal microarray (CMA) has allowed identification of copy number variations (CNVs) in lung and colorectal cancers in great detail, and next-generation sequencing (NGS) is used extensively to analyze the genome of cancers for molecular subtyping and use of molecularly guided therapies. The main objective of this study was to evaluate the utility of combining CMA and NGS for a comprehensive genomic assessment of lung and colorectal adenocarcinomas, especially for detecting drug targets. We compared the results from NGS and CMA data from 60 lung and 51 colorectal tumors. From CMA analysis, 33% were amplified, 89% showed gains, 75% showed losses and 41% demonstrated loss of heterozygosity; pathogenic variants were identified in 81% of colon and 67% lung specimens through NGS. KRAS mutations commonly occurred with loss in TP53 and there was significant loss of BRCA1 and NF1 among male patients with lung cancer. For clinically actionable targets, 23% had targetable CNVs when no pathogenic variants were detected by NGS. The data thus indicate that combining the two approaches provides significant benefit in a routine clinical setting not available by NGS alone., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
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8. Lack of correlation between HERV-K expression and HIV-1 viral load in plasma specimens.
- Author
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Esqueda D, Xu F, Moore Y, Yang Z, Huang G, Lennon PA, Hu PC, and Dong J
- Subjects
- DNA Primers genetics, Electrophoresis, Agar Gel, HIV Infections virology, Humans, RNA, Viral isolation & purification, Reverse Transcriptase Polymerase Chain Reaction, Viral Load, Endogenous Retroviruses metabolism, HIV Infections blood, HIV-1 metabolism, RNA, Viral blood
- Abstract
HERV-K viral RNA has been reported in plasma specimens of HIV-1 infected individuals. Emerging data support the regulation and functional interaction between HERV-K and HIV-1, which warrant development of accurate HERV-K assays to evaluate HERV-K activation. In this study, we examined HERV-K RNA expression after careful removal of "contaminating" cellular DNA using DNase I. We found that DNase I digestion effectively reduced HERV-K RT-PCR positive signal. We also found that levels of HERV-K expression did not correlate with HIV-1 viral load. Our study is in agreement with the published studies on HERV-K activation in HIV-1 positive plasma specimens, and in addition, calls for careful removal of cellular DNA to accurately evaluate HERV-K RNA expression.
- Published
- 2013
9. Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma.
- Author
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Ramirez E, Singh RR, Kunkalla K, Liu Y, Qu C, Cain C, Multani AS, Lennon PA, Jackacky J, Ho M, Dawud S, Gu J, Yang S, Hu PC, and Vega F
- Subjects
- Biomarkers, Tumor genetics, Blotting, Western, Cell Proliferation, Hedgehog Proteins genetics, Humans, In Situ Hybridization, Fluorescence, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology, NF-kappa B genetics, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins c-akt genetics, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Receptors, G-Protein-Coupled genetics, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Smoothened Receptor, Transcription Factors genetics, Tumor Cells, Cultured, Zinc Finger Protein GLI1, Biomarkers, Tumor metabolism, Hedgehog Proteins metabolism, Lymphoma, Large B-Cell, Diffuse metabolism, NF-kappa B metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Receptors, G-Protein-Coupled metabolism, Transcription Factors metabolism
- Abstract
Hedgehog (Hh) signaling pathway is activated in diffuse large B-cell lymphoma (DLBCL). Genetic abnormalities that explain activation of Hh signaling in DLBCL are unknown. We investigate the presence of amplifications of Hh genes that might result in activation of this pathway in DLBCL. Our data showed few extra copies of GLI1 and SMO due to chromosomal aneuploidies in a subset of DLBCL cell lines. We also showed that pharmacologic inhibition of PI3K/AKT and NF-κB pathways resulted in decreased expression of GLI1 and Hh ligands. In conclusion, our data support the hypothesis that aberrant activation of Hh signaling in DLBCL mainly results from integration of deregulated oncogenic signaling inputs converging into Hh signaling., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
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10. Is monosomy 21 rare? Seven early miscarriages including one mosaic 45,XX,-21/44,X,-21 in a single study population.
- Author
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Hardy P, Bryan J, Hardy R, Lennon PA, and Hardy K
- Subjects
- Female, Humans, Pregnancy, Chromosomes, Human, Pair 21, Monosomy, Stillbirth genetics
- Published
- 2012
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11. Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma.
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Lin P, Dickason TJ, Fayad LE, Lennon PA, Hu P, Garcia M, Routbort MJ, Miranda R, Wang X, Qiao W, and Medeiros LJ
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- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Burkitt Lymphoma drug therapy, Burkitt Lymphoma mortality, Burkitt Lymphoma pathology, Female, Humans, Lymphoma, B-Cell genetics, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse mortality, Lymphoma, Large B-Cell, Diffuse pathology, Male, Middle Aged, Prognosis, Treatment Outcome, Burkitt Lymphoma genetics, Gene Rearrangement, Genes, myc, Lymphoma, B-Cell classification, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
Background: B-cell lymphoma, Unclassifiable with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, for convenience referred to here as unclassifiable B-cell lymphoma, is a category in the 2008 World Health Organization system used for a group of histologically aggressive neoplasms that are difficult to classify definitively. Currently, there is no established standard therapy for these neoplasms., Methods: The authors assessed MYC status and correlated it with treatment response and outcome in a group of 52 patients with unclassifiable B-cell lymphoma treated with either a standard DLBCL regimen (R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone-related therapy]) or more intensive regimens, such as R-hyper-CVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine). The regimens were selected by the treating clinicians based on the overall clinical and pathological findings., Results: Thirty (58%) unclassifiable B-cell lymphomas had MYC abnormalities (MYC(+) ) including 27 with rearrangement, 2 with amplification, and 1 with both. The MYC(+) and MYC(-) groups were similar in their age distribution and International Prognostic Index scores. Progression-free survival of patients with MYC(+) unclassifiable B-cell lymphoma treated initially with R-CHOP was significantly worse than patients treated with R-hyper-CVAD (P = .0358). In contrast, for the MYC(-) unclassifiable B-cell lymphoma group, some patients responded to R-CHOP, and others were refractory to R-hyper-CVAD., Conclusions: MYC aberrations are common in unclassifiable B-cell lymphoma. The presence of MYC aberrations identifies a patient subset that requires more aggressive therapy than R-CHOP. In contrast, MYC(-) unclassifiable B-cell lymphoma patients responded variably to either R-CHOP or aggressive therapy, and the latter showed no survival advantage., (Copyright © 2011 American Cancer Society.)
- Published
- 2012
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12. B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome.
- Author
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Li S, Lin P, Fayad LE, Lennon PA, Miranda RN, Yin CC, Lin E, and Medeiros LJ
- Subjects
- Adolescent, Adult, Aged, B-Lymphocytes pathology, Female, Genetic Predisposition to Disease, Germinal Center pathology, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Kaplan-Meier Estimate, Lymphoma, B-Cell classification, Lymphoma, B-Cell immunology, Lymphoma, B-Cell mortality, Lymphoma, B-Cell pathology, Male, Middle Aged, Phenotype, Prognosis, Retrospective Studies, Texas, Time Factors, Young Adult, B-Lymphocytes immunology, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 18, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Genes, Immunoglobulin Heavy Chain, Germinal Center immunology, Immunophenotyping, Lymphoma, B-Cell genetics, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-myc genetics, Translocation, Genetic
- Abstract
B-cell lymphomas with MYC/8q24 rearrangement and IGH@BCL2/t(14;18)(q32;q21), also known as double-hit or MYC/BCL2 B-cell lymphomas, are uncommon neoplasms. We report our experience with 60 cases: 52 MYC/BCL2 B-cell lymphomas and 8 tumors with extra MYC signals plus IGH@BCL2 or MYC rearrangement plus extra BCL2 signals/copies. There were 38 men and 22 women with a median age of 55 years. In all, 10 patients had antecedent/concurrent follicular lymphoma. Using the 2008 World Health Organization classification, there were 33 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (henceforth referred to as unclassifiable, aggressive B-cell lymphoma), 23 diffuse large B-cell lymphoma, 1 follicular lymphoma grade 3B, 1 follicular lymphoma plus diffuse large B-cell lymphoma, 1 B-lymphoblastic lymphoma, and 1 composite diffuse large B-cell lymphoma with B-lymphoblastic lymphoma. Using older classification systems, the 33 unclassifiable, aggressive B-cell lymphomas most closely resembled Burkitt-like lymphoma (n=24) or atypical Burkitt lymphoma with BCL2 expression (n=9). Of 48 cases assessed, 47 (98%) had a germinal center B-cell immunophenotype. Patients were treated with standard (n=23) or more aggressive chemotherapy regimens (n=34). Adequate follow-up was available for 57 patients: 26 died and 31 were alive. For the 52 patients with MYC/BCL2 lymphoma, the median overall survival was 18.6 months. Patients with antecedent/concurrent follicular lymphoma had median overall survival of 7.8 months. Elevated serum lactate dehydrogenase level, ≥2 extranodal sites, bone marrow or central nervous system involvement, and International Prognostic Index >2 were associated with worse overall survival (P<0.05). Morphological features did not correlate with prognosis. Patients with neoplasms characterized by extra MYC signals plus IGH@BCL2 (n=6) or MYC rearrangement with extra BCL2 signals (n=2) had overall survival ranging from 1.7 to 49 months, similar to patients with MYC/BCL2 lymphomas. We conclude that MYC/BCL2 lymphomas are clinically aggressive, irrespective of their morphological appearance, with a germinal center B-cell immunophenotype. Tumors with extra MYC signals plus IGH@BCL2 or MYC rearrangement plus extra BCL2 signals, respectively, appear to behave as poorly as MYC/BCL2 lymphomas, possibly expanding the disease spectrum.
- Published
- 2012
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13. A model for rewarding professional growth in the diagnostic molecular oncology laboratory.
- Author
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Lennon PA, Deleon E, Reynolds A, Pulido L, Lewing C, Mehta P, Biscanin S, Hai S, Bowman C, Galbincea J, Jakacky J, and Hu P
- Abstract
The University of Texas M.D. Anderson Cancer Center (UTMDACC), Department of Pathology and Laboratory Medicine is committed to the endless pursuit of innovative research, education, training and administration for the prevention, diagnosis and clinical management of cancer and associated diseases. The molecular genetic technology professional development model promotes personal development, recognizes increased competencies, and sets high standards for all skills and services provided. There are four competency levels that comprise our Professional Development Model (PDM): Discovery, Application, Maturation, and Expert. The skill, knowledge, education, and certification requirements for each level are defined based on the business needs of each lab. When a genetic technologist successfully completes all skills, knowledge, proficiency, education and certification requirements within the appropriate time frame for a particular competency level, his/her salary would be adjusted to the entry point for the competency level he/she has completed.
- Published
- 2011
14. Variations in MALT1 Gene Disruptions Detected by FISH in 109 MALT Lymphomas Occurring in Different Primary Sites.
- Author
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Mulligan S, Hu P, Murphy A, Han J, Tam M, Lin P, Konoplev S, and Lennon PA
- Abstract
Mucosa-associated lymphoid tissue (MALT) lymphoma is a type of B-cell non-Hodgkin lymphoma that can originate in the gastrointestinal (GI) tract, thyroid, breasts, lungs, and skin. The most common genetic abnormality occurring in MALT lymphomas involves t(11;18)(q21;q21) in the gene MALT1. This translocation results in a chimeric fusion product between the genes ATI2 and MALT1, which generates a survival advantage in the lymphoma cells. The MALT1 disruption is more common in some MALT lymphomas, distinguished by site, than others. If identified, this variation in frequency could affect treatment courses and outcomes for each type of MALT lymphoma. The study included 109 MALT lymphoma sample specimens. The sample paraffin-embedded slides were pretreated, hybridized for FISH using a MALT1 break-apart probe, post-washed, and viewed using a fluorescent microscope. On each slide, 100 individual cells were counted by two independent readers, totaling 200 cells per case, and the percentage of cells containing a translocation within each sample was recorded. A conservative threshold of 8% was used to make a positive call. There were a total of 18 positive results in the 109 samples tested. The tissue specimens tested that yielded positive results include the colon (62.5%), lung (57.14%), skin (25%), eyelid/lacrimal gland (16.67%), stomach (6.45%), kidney (50%), and thyroid (100%). The sites that yielded only negative results (0%) include the breast, salivary gland, salivary gland/parotid, soft tissue/skin, conjunctiva/orbital, small intestine, nasal, and epidural mass. As hypothesized, a variation in the MALT1 disruption was found. This is the first study to examine MALT1 disruption in the soft tissue, nasal, and epidural mass. The positive results of this study, specifically the results for the colon and lung, and the negative breast and salivary gland results are consistent with previous studies examining the genetic aberrations in MALT lymphomas. These results indicate that MALT lymphoma at different locations differentially display MALT1 disruption, and these disruptions may be responsible for the variance in patient response to therapy. Surgery, radiation therapy, and/or administration of cladribine (2CdA) result in the best outcomes in treating MALT lymphomas with MALT1 disruption.
- Published
- 2011
15. Distinct patterns of cytogenetic and clinical progression in chronic myeloproliferative neoplasms with or without JAK2 or MPL mutations.
- Author
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Millecker L, Lennon PA, Verstovsek S, Barkoh B, Galbincea J, Hu P, Chen SS, and Jones D
- Subjects
- Chronic Disease, Codon, Disease Progression, Gene Dosage, Humans, Karyotyping, Mutation, Primary Myelofibrosis therapy, Thrombocythemia, Essential therapy, Janus Kinase 2 genetics, Primary Myelofibrosis genetics, Receptors, Thrombopoietin genetics, Thrombocythemia, Essential genetics
- Abstract
Chronic myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET) and primary myelofibrosis (PMF), result from interactions between initiating growth factor mutations and secondary genomic changes. Codon 617 mutation of the JAK2 kinase is found in 40-50% of ET/PMF, whereas the mutation of codon 515 in the JAK2-linked thrombopoietin receptor MPL is found in approximately 20% of JAK2-unmutated cases of ET and PMF. Using quantitative mutation assays, we compared patterns of clinical and cytogenetic progression in MPL-mutated MPN (n=21) to those with JAK2 V617F mutation (n=383) or neither mutation (n=109). Among patients with MPL mutations, ET was seen in 9 and PMF in 12. Median mutation levels in pretreatment ET samples were significantly higher for MPL-mutated cases (60%) than for JAK2-mutated cases (24%; P=0.01), as was presentation with anemia. Differential genomic changes included +9 in JAK2-mutated cases and chromosome 1 alterations in MPL-mutated ones, implicating dosage effects related to gene copy number. Decreases in the levels of MPL mutation were seen in sequential marrow samples from some patients under treatment with biologic therapies, but not in those treated with kinase inhibitors, consistent with selective response of the MPL-mutated clone similar to the responses seen in JAK2-mutated MPN., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
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16. Examining Hedgehog pathway genes GLI3, SHH, and PTCH1 and the p53 target GLIPR1/GLIPR1L1/GLIPR1L2 gene cluster using fluorescence in situ hybridization uncovers GLIPR1/GLIPR1L1/GLIPR1L2 deletion in 9% of patients with multiple myeloma.
- Author
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Tam M, Lin P, Hu P, and Lennon PA
- Abstract
Mutations in genes regulating cell cycle and apoptosis are considered major culprits for the malignant transformation of cancer cells. Aberrant activation of the Hedgehog (HH) signaling pathway which primarily regulates genes involved in cell growth, proliferation, survival and apoptosis has been demonstrated in multiple myeloma. Mutations resulting in defective components of the p53 pathway, which serves a critical role in mediating cellular stress response by triggering DNA repair, cell cycle arrest, senescence and apoptosis, have also been identified. This study focuses on detecting copy number variations for the GLIPR1/GLIPR1L1/GLIPR1L2 gene cluster of the p53 pathway and three elements of the HH pathway, SHH, PTCH1 and GLI3 in multiple myeloma (MM) using fluorescence in situ hybridization (FISH). In eighteen samples, there was no evidence of abnormal copy number for PTCH1, GLI3 or SHH. Thus, it is unlikely that copy number variations of these genes are linked to multiple myeloma. However, a deletion of the GLIPR1/GLIPR1L1/ GLIPR1L2 gene cluster, all p53 targets, was found in three of 32 samples (9.4%) indicating that these deleted genes may have significant implications in MM. Further studies should be performed to determine the role of the GLIPR1/GLIPR1L1/GLIPR1L2 gene cluster in the pathogenesis of multiple myeloma.
- Published
- 2010
17. Professional development model for cytogenetic technologists at University of Texas-M.D. Anderson Cancer Center sets high standards.
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Lennon PA, Lovshe D, Deleon E, Reynolds A, Pulido L, Cheong S, Zhao L, Frimpong L, Harper E, Van Fleet T, Honore L, and Hu P
- Published
- 2010
18. Chronic myeloid leukemia in blast phase associated with t(3;8)(q26;q24).
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Lin P, Lennon PA, Yin CC, and Abruzzo LV
- Subjects
- Female, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Middle Aged, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 8, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Translocation, Genetic
- Abstract
We previously reported a recurrent t(3;8)(q26;q24) translocation involving EVI1 in five patients with myelodysplastic syndrome or acute myeloid leukemia. Here we report the same structural abnormality in a case of chronic myeloid leukemia in blast phase. The t(3;8)(q26;q24) occurred several months after the initial diagnosis of chronic myeloid leukemia, while the patient was being treated with a tyrosine kinase inhibitor. We confirmed rearrangement of EVI1 by fluorescence in situ hybridization assay using a dual-color break-apart probe set that spans the EVI1 region. Our findings demonstrate that, similar to other recurrent translocations involving 3q26, such as t(3;3) and t(3;21), the t(3;8)(q26;q24) is implicated not only in myelodysplastic syndrome and acute myeloid leukemia, but also in progression of chronic myeloid leukemia. These findings extend the known disease spectrum associated with this cytogenetic aberration.
- Published
- 2009
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19. Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma.
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Singh RR, Cho-Vega JH, Davuluri Y, Ma S, Kasbidi F, Milito C, Lennon PA, Drakos E, Medeiros LJ, Luthra R, and Vega F
- Subjects
- Anaplastic Lymphoma Kinase, Cell Cycle physiology, Cell Line, Tumor, Cell Survival physiology, Enzyme Activation, Gene Amplification, Hedgehog Proteins antagonists & inhibitors, Hedgehog Proteins biosynthesis, Hedgehog Proteins genetics, Humans, Immunohistochemistry, Jurkat Cells, Lymphoma, Large-Cell, Anaplastic enzymology, Lymphoma, Large-Cell, Anaplastic genetics, Lymphoma, Large-Cell, Anaplastic pathology, Phosphatidylinositol 3-Kinases metabolism, Protein-Tyrosine Kinases biosynthesis, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins c-akt metabolism, Receptor Protein-Tyrosine Kinases, Signal Transduction, Transcription Factors antagonists & inhibitors, Transcription Factors biosynthesis, Transcription Factors genetics, Transcription Factors metabolism, Transcription, Genetic, Transfection, Zinc Finger Protein GLI1, Hedgehog Proteins metabolism, Lymphoma, Large-Cell, Anaplastic metabolism
- Abstract
Deregulation of the sonic hedgehog (SHH) signaling pathway has been implicated in several cancers but has not been explored in T-cell lymphomas. Here, we report that the SHH/GLI1 signaling pathway is activated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL). We show that SHH, but not its transcriptional effector GLI1, is amplified in ALK+ ALCL tumors and cell lines, and that SHH and GLI1 proteins are highly expressed in ALK+ ALCL tumors and cell lines. We also show that inhibition of SHH/GLI1 signaling with cyclopamine-KAAD, as well as silencing GLI1 gene expression by small interfering (si)RNA, decreased cell viability and clonogenicity of ALK+ ALCL cells. Transfection of wild-type or mutant NPM-ALK into 293T cells showed that only wild-type NPM-ALK increased GLI1 protein levels and activated SHH/GLI1 signaling as shown by increase of CCND2 mRNA levels. Inhibition of ALK tyrosine kinase and phosphatidylinositol 3-kinase (PI3K)/AKT or forced expression of pAKT down-regulated or up-regulated SHH/GLI1 signaling, respectively. Inhibition of GSK3beta in 293T cells also increased protein levels of GLI1. In conclusion, the SHH/GLI1 signaling pathway is activated in ALK+ ALCL. SHH/GLI1 activation is the result of SHH gene amplification and is further mediated by NPM-ALK through activation of PI3K/AKT and stabilization of GLI1 protein. There is a positive synergistic effect between the SHH/GLI1 and PI3K/AKT pathways that contributes to the lymphomagenic effect of NPM-ALK.
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- 2009
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20. Translocation (18;22)(q21;q11) in B-cell lymphomas: a report of 4 cases and review of the literature.
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Lin P, Jetly R, Lennon PA, Abruzzo LV, Prajapati S, and Medeiros LJ
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- Aged, Fatal Outcome, Female, Gene Rearrangement, B-Lymphocyte, Genes, bcl-2, Humans, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Lymphoma, B-Cell drug therapy, Male, Middle Aged, Translocation, Genetic, Chromosomes, Human, Pair 18, Chromosomes, Human, Pair 22, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoma, B-Cell genetics
- Abstract
Follicular lymphomas characteristically carry t(14;18)(q32;q21) which results in IGH-BCL-2 fusion. Variant translocations that juxtapose the BCL-2 gene with the immunoglobulin kappa (2p11) and lambda (22q11) light chain genes are rare. We report 4 cases of B-cell lymphoma/leukemia associated with t(18;22)(q21;q11). The t(18;22)(q21;q11) was the sole aberration identified by conventional cytogenetics in 2 cases. Three cases were classified as chronic lymphocytic leukemia, and one as follicular lymphoma based on morphology and immunophenotype. Fluorescence in situ hybridization analysis was performed on all 4 cases using a BCL-2 breakapart probe. The BCL-2 gene was rearranged in all cases. Immunoglobulin lambda light chain gene rearrangement was shown in 3 cases using bacterial artificial chromosome probes spanning the variable and constant clusters of the IGlambda gene. Each case was negative for MALT-1 rearrangement using a MALT-1 breakapart probe. These cases illustrate that t(18;22)(q21;q11) is more commonly observed in chronic lymphocytic leukemia and may represent either an initial or secondary genetic event.
- Published
- 2008
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21. Validation of a targeted DNA microarray for the clinical evaluation of recurrent abnormalities in chronic lymphocytic leukemia.
- Author
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Patel A, Kang SH, Lennon PA, Li YF, Rao PN, Abruzzo L, Shaw C, Chinault AC, and Cheung SW
- Subjects
- Chromosomes, Human genetics, Gene Dosage genetics, Genome, Human genetics, Genomic Instability genetics, Humans, In Situ Hybridization, Fluorescence, Pilot Projects, Sensitivity and Specificity, Chromosome Aberrations, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Oligonucleotide Array Sequence Analysis methods
- Abstract
Recurrent genomic alterations, mainly losses and gains of specific chromosomes and/or regions, in chronic lymphocytic leukemia (CLL) are recognized as important independent predictors of prognosis and disease progression. The current standard clinical practice for identifying these alterations is chromosome analysis and in situ hybridization with probes targeting 4-5 chromosome regions. We sought to apply array comparative genomic hybridization (array-CGH) technology for the simultaneous detection of genomic imbalances of all loci implicated in CLL. DNA from enriched B-cells from CLL patients were analyzed by array-CGH on a customized CLL BAC array. Copy number changes were detected in 87% of samples with a sensitivity of 100% in samples with clonal abnormalities present in at least 23% of the cells. Furthermore, in nine cases genomic alterations were observed that were undetectable by standard cytogenetic and/or FISH analyses. One of these patients had a 13q14 deletion that was missed by the clinical CLL FISH panel probe set. Our results suggest that a subset of potentially significant genomic alterations in CLL is being missed by the current available techniques. Furthermore, this pilot study clearly shows the robustness, high sensitivity, and high specificity for the targeted CLL microarray analysis as well as the potential for use in routine screening in CLL., ((c) 2007 Wiley-Liss, Inc.)
- Published
- 2008
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22. Splenic marginal zone lymphomas are characterized by loss of interstitial regions of chromosome 7q, 7q31.32 and 7q36.2 that include the protection of telomere 1 (POT1) and sonic hedgehog (SHH) genes.
- Author
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Vega F, Cho-Vega JH, Lennon PA, Luthra MG, Bailey J, Breeden M, Jones D, Medeiros LJ, and Luthra R
- Subjects
- Aged, Comparative Genomic Hybridization methods, DNA Mutational Analysis, DNA, Neoplasm genetics, DNA, Neoplasm isolation & purification, Female, Hedgehog Proteins genetics, Hedgehog Proteins physiology, Humans, In Situ Hybridization, Fluorescence, Lymphatic Diseases physiopathology, Lymphoma, B-Cell, Marginal Zone physiopathology, Male, Middle Aged, Nucleic Acid Hybridization methods, Oligonucleotide Array Sequence Analysis methods, Reverse Transcriptase Polymerase Chain Reaction, Shelterin Complex, Splenic Neoplasms physiopathology, Telomere genetics, Telomere-Binding Proteins genetics, Telomere-Binding Proteins physiology, Chromosomes, Human, Pair 7 genetics, Lymphatic Diseases genetics, Lymphoma, B-Cell, Marginal Zone genetics, Splenic Neoplasms genetics
- Abstract
To further characterize the genotypic features of splenic (S) and nodal (N) marginal zone lymphomas (MZL) we compared eight SMZL and five NMZL by array-based comparative genomic hybridization (aCGH). Arbitrarily, aberrations were divided into major imbalances, defined as gains or losses involving five or more contiguous genetic loci, and minor imbalances, defined as those involving four or fewer loci. SMZL, but not NMZL, demonstrated major imbalances. These included deletions involving various lengths of 7q (three cases), and 14q23q24 (one case) and gains of 9p13p21 (one case), 13q21q33 (one case) and 16p13.1 (one case). Common minor imbalances in SMZL were: loss of sonic hedgehog gene (SHH) at 7q36.2 (four cases), loss of protection of telomere 1 gene (POT1) at 7q31.32 (three cases), and gain of glioma associated oncogene 1 (GLI1) at 12q13.2 (three cases). Common minor alterations in NMZL were: loss of the fas-associated via death domain gene (FADD) at 11q13.2 (three cases) and gain of GLI1 (five cases). In conclusion, SMZL, but not NMZL, demonstrates large genomic imbalances and frequent loss of the 7q31.32 and 7q36.2 regions involving POT1 and SHH, respectively. In NMZL, loss of FADD and gain of GLI1 are frequent events.
- Published
- 2008
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23. Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies.
- Author
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Quintás-Cardama A, Tong W, Manshouri T, Vega F, Lennon PA, Cools J, Gilliland DG, Lee F, Cortes J, Kantarjian H, and Garcia-Manero G
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Adult, Animals, Apoptosis drug effects, Benzamides, Blotting, Western, Cell Cycle drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Dasatinib, Female, Humans, Imatinib Mesylate, In Situ Hybridization, Fluorescence, Leukemia, Experimental enzymology, Leukemia, Experimental genetics, Leukemia-Lymphoma, Adult T-Cell enzymology, Leukemia-Lymphoma, Adult T-Cell genetics, Male, Mice, Mice, Inbred NOD, Mice, SCID, Nuclear Proteins metabolism, Oncogene Proteins, Fusion metabolism, Phosphorylation drug effects, Piperazines therapeutic use, Pyrimidines therapeutic use, Reverse Transcriptase Polymerase Chain Reaction, STAT5 Transcription Factor metabolism, Thiazoles therapeutic use, Tumor Cells, Cultured, Leukemia, Experimental drug therapy, Leukemia-Lymphoma, Adult T-Cell drug therapy, Oncogene Proteins, Fusion genetics, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases antagonists & inhibitors
- Abstract
Amplification of the NUP214-ABL1 oncogene can be detected in patients with T cell acute lymphoblastic leukemia (T-ALL). We screened 29 patients with T cell malignancies for the expression of NUP214-ABL1 by reverse transcription-polymerase chain reaction (RT-PCR). NUP214-ABL1 was detected in three (10%) patients. These results were confirmed by fluorescence in situ hybridization techniques. We also studied the activity of imatinib, nilotinib and dasatinib against the human NUP214-ABL1-positive cell lines PEER and BE-13. All three tyrosine kinase inhibitors decreased the viability of PEER and BE-13 cells, but nilotinib and dasatinib had >1-log lower IC(50) values than imatinib (P<0.001). In contrast, the NUP214-ABL-negative T-ALL cell line Jurkat, was remarkably resistant to tyrosine kinase inhibition. The inhibition of cellular proliferation was associated with time-dependent induction of apoptosis and inhibition of ABL, CrKL and STAT5 phosphorylation. Moreover, dasatinib was active in a NUP214-ABL1-positive leukemia xenograft murine model and in marrow lymphoblasts from a patient with NUP214-ABL1-positive T-ALL. On the basis of these results, ABL1 kinase inhibitors warrant clinical investigation in patients with NUP214-ABL1-positive T-cell malignancies.
- Published
- 2008
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24. Therapy may unmask hypoplastic myelodysplastic syndrome that mimics aplastic anemia.
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Konoplev S, Medeiros LJ, Lennon PA, Prajapati S, Kanungo A, and Lin P
- Subjects
- Adult, Aged, Anemia, Aplastic blood, Anemia, Aplastic drug therapy, Anemia, Aplastic genetics, Bone Marrow Transplantation, Cytogenetic Analysis, Diagnosis, Differential, Female, Hematologic Tests, Humans, Immunologic Factors therapeutic use, In Situ Hybridization, Fluorescence, Karyotyping, Male, Middle Aged, Myelodysplastic Syndromes blood, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics, Retrospective Studies, Anemia, Aplastic diagnosis, Anemia, Aplastic therapy, Chromosomes, Human, Pair 7, Monosomy, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes therapy
- Abstract
Background: Rarely, patients who present with pancytopenia and are diagnosed initially with aplastic anemia (AA) subsequently develop a myelodysplastic syndrome (MDS). There has been controversy regarding whether the initial diagnosis of AA is correct or whether these patients have hypocellular MDS at the onset of pancytopenia., Methods: The authors studied bone marrow (BM) specimens from patients who were diagnosed initially with AA and subsequently with MDS from a cohort of 128 consecutive patients who had AA during the period from 1993 to 2004. Cytogenetic and fluorescence in situ hybridization (FISH) analyses were performed to assess for monosomy 7 retrospectively in a subset of patients., Results: Twelve patients were identified (age range, 26-79 years). At the time they were diagnosed with AA, there was no evidence of dysplasia, the median BM cellularity was 5% (range, from <1% to 15%), and all patients had a normal karyotype. Therapy for 11 patients included immunomodulating agents, which were accompanied by growth factors in 4 patients and 1 patient underwent BM transplantation. One patient received growth factors only. The median interval to the diagnosis of MDS was 9 months (range, 2-43 months). The median BM cellularity was 30% (range, 5-90%), and dysplastic changes were observed in all patients. Nine patients had an abnormal karyotype, and monosomy 7 was the most common abnormality (n = 5 patients). FISH detected monosomy 7 in 6 samples at the time MDS was diagnosed and in 2 samples at the time AA was diagnosed., Conclusions: The detection of monosomy 7 in specimens that were considered AA and the short time interval to a subsequent diagnosis of MDS suggests that these patients had hypoplastic MDS at the onset of pancytopenia. Therapy may allow the detection of MDS by enhancing cell growth.
- Published
- 2007
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25. Aberrant EVI1 expression in acute myeloid leukemias associated with the t(3;8)(q26;q24).
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Lennon PA, Abruzzo LV, Medeiros LJ, Cromwell C, Zhang X, Yin CC, Kornblau SM, Konopieva M, and Lin P
- Subjects
- Acute Disease, Blotting, Western, Chromosome Mapping, Humans, In Situ Hybridization, Fluorescence, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, MDS1 and EVI1 Complex Locus Protein, Proteins genetics, Proto-Oncogene Mas, Proto-Oncogene Proteins c-myc genetics, RNA, Long Noncoding, Reverse Transcriptase Polymerase Chain Reaction, Chromosomes, Human, Pair 3 genetics, Chromosomes, Human, Pair 8 genetics, DNA-Binding Proteins genetics, Gene Expression Regulation, Leukemic, Leukemia, Myeloid genetics, Proto-Oncogenes genetics, Transcription Factors genetics, Translocation, Genetic
- Abstract
EVI is a proto-oncogene that is activated in acute myeloid leukemia with chromosomal rearrangements that map to chromosome 3q26. We previously reported the clinicopathologic features of five cases of acute myeloid leukemia carrying t(3;8)(q26;q24). Using fluorescence in situ hybridization analysis, we demonstrate in the current study that the breakpoint on chromosome 3 is at EVI1/MDS1, and the breakpoint on chromosome 8 is just distal to the PVT1 oncogene homolog, a C-MYC activator in mice. The breakpoint on chromosome 8 was detected between the components of the LSI MYC dual-color break-apart rearrangement probe. Reverse-transcriptase polymerase chain reaction assay showed expression of EVI1 in all four cases analyzed, and DNA sequence analysis confirmed the findings. Reverse transcriptase polymerase chain reaction assay also demonstrated the expression of PVT1 and C-MYC in all four cases assessed. Western blot analysis detected EVI1 in one case analyzed. We conclude that the t(3;8)(q26;q24) results in deregulated EVI1 expression, similar to other balanced or unbalanced chromosomal translocations involving chromosome 3q26.
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- 2007
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26. Deletion of 7q31.1 supports involvement of FOXP2 in language impairment: clinical report and review.
- Author
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Lennon PA, Cooper ML, Peiffer DA, Gunderson KL, Patel A, Peters S, Cheung SW, and Bacino CA
- Subjects
- Autistic Disorder genetics, Child, Chromosome Mapping, Humans, Male, Microsatellite Repeats, Pedigree, Chromosome Deletion, Chromosomes, Human, Pair 7, Forkhead Transcription Factors genetics, Language Disorders genetics, Speech Disorders genetics
- Abstract
We report on a young male with moderate mental retardation, dysmorphic features, and language delay who is deleted for 7q31.1-7q31.31. His full karyotype is 46,XY,der(7)del(7)(q31.1q31.31)ins(10;7)(q24.3;q31.1q31.31)mat. This child had language impairment, including developmental verbal dyspraxia, but did not meet criteria for autism according to standardized ADOS testing. Our patient's deletion, which is the smallest reported deletion including FOXP2, adds to the body of evidence that supports the role of FOXP2 in speech and language impairment, but not in autism. A reported association between autism and deletions of WNT2, a gene also deleted in our patient, is likewise not supported by our case. Previously, fine mapping with microsatellites markers within in a large three-generation family, in which half the members had severe specific language impairment, aided the localization of the SPCH1 locus to 7q31 within markers D7S2459 (107.1 Mb) and D7S643 (120.5 Mb). Additionally, chromosome rearrangement of 7q31 and mutational analyses have supported the growing evidence that FOXP2, a gene within the SPCH1 region, is involved with speech and language development. It is unclear however whether the AUTS1 (autistic spectrum 1) locus, highly linked to 7q31, overlaps with the SPCH1 and FOXP2., (Copyright 2007 Wiley-Liss, Inc.)
- Published
- 2007
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27. A novel 8.5 MB dup(1)(p34.1p34.3) characterized by FISH in a child presenting with congenital heart defect and dysmorphic features.
- Author
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Lennon PA, Boerkoel CF, Plunkett K, Soukam S, Cheung SW, and Patel A
- Subjects
- Child, Preschool, Chromosome Banding, Female, Humans, In Situ Hybridization, Fluorescence, Chromosome Aberrations, Chromosomes, Human, Pair 1, Heart Defects, Congenital diagnosis, Heart Defects, Congenital genetics
- Abstract
Chromosome duplications involving 1p are rarely reported but are apparently associated with short survival as well as congenital malformations and impaired development. Several of these have had congenital heart defects, although too few patients have been reported with similar breakpoints to characterize a syndrome. We present a girl with a novel interstitial duplication in the short arm of chromosome 1 [46,XX,dup(1)(p34.1p34.3)]. She presented with congenital heart defects at 1 month and by 1 year of age manifested delayed acquisition of motor milestones and subsequently of language milestones. By breakpoint-mapping using FISH analysis, we determined that her 1p duplication spans 8.5 megabases. Her 1p duplication is the smallest reported to date to contain 1p34 in patients with congenital heart defect due to abnormalities of heart looping during development. Thus, her 8.5 MB duplication provides a target region to search for a potentially dosage-sensitive gene(s) causing abnormal heart looping when duplicated. Two patients have been reported with duplication including 1p34 but without congenital heart defect, and their duplications span all but the distal approximately 2 MB segment duplicated in our patient. Thus, within our patient's 8.5 MB target region for a dosage sensitive gene leading to looping abnormalities (and thereby congenital heart defect), the distal 2 MB region might well be the region to begin the search.
- Published
- 2006
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28. Array-based comparative genomic hybridization facilitates identification of breakpoints of a novel der(1)t(1;18)(p36.3;q23)dn in a child presenting with mental retardation.
- Author
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Lennon PA, Cooper ML, Curtis MA, Lim C, Ou Z, Patel A, Cheung SW, and Bacino CA
- Subjects
- Child, Chromosome Banding, Chromosome Breakage genetics, Female, Genome, Human, Humans, In Situ Hybridization, Fluorescence, Intellectual Disability pathology, Karyotyping, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 8 genetics, Intellectual Disability genetics, Nucleic Acid Hybridization methods, Translocation, Genetic
- Abstract
Monosomy of distal 1p36 represents the most common terminal deletion in humans and results in one of the most frequently diagnosed mental retardation syndromes. This deletion is considered a contiguous gene deletion syndrome, and has been shown to vary in deletion sizes that contribute to the spectrum of phenotypic anomalies seen in patients with monosomy 1p36. We report on an 8-year-old female with characteristics of the monosomy 1p36 syndrome who demonstrated a novel der(1)t(1;18)(p36.3;q23). Initial G-banded karyotype analysis revealed a deleted chromosome 1, with a breakpoint within 1p36.3. Subsequent FISH and array-based comparative genomic hybridization not only confirmed and partially characterized the deletion of chromosome 1p36.3, but also uncovered distal trisomy for 18q23. In this patient, the duplicated 18q23 is translocated onto the deleted 1p36.3 region, suggesting telomere capture. Molecular characterization of this novel der(1)t(1;18)(p36.3;q23), guided by our clinical array-comparative genomic hybridization, demonstrated a 3.2 Mb terminal deletion of chromosome 1p36.3 and a 200 kb duplication of 18q23 onto the deleted 1p36.3, presumably stabilizing the deleted chromosome 1. DNA sequence analysis around the breakpoints demonstrated no homology, and therefore this telomere capture of distal 18q is apparently the result of a non-homologous recombination. Partial trisomy for 18q23 has not been previously reported. The importance of mapping the breakpoints of all balanced and unbalanced translocations found in the clinical laboratory, when phenotypic abnormalities are found, is discussed., (Copyright 2006 Wiley-Liss, Inc.)
- Published
- 2006
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29. WAGR(O?) syndrome and congenital ptosis caused by an unbalanced t(11;15)(p13;p11.2)dn demonstrating a 7 megabase deletion by FISH.
- Author
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Lennon PA, Scott DA, Lonsdorf D, Wargowski DS, Kirkpatrick S, Patel A, and Cheung SW
- Subjects
- Abnormalities, Multiple pathology, Chromosome Banding, Chromosome Deletion, Female, Humans, In Situ Hybridization, Fluorescence, Infant, Karyotyping, Obesity pathology, Abnormalities, Multiple genetics, Blepharoptosis pathology, Chromosomes, Human, Pair 11 genetics, Chromosomes, Human, Pair 15 genetics, Translocation, Genetic, WAGR Syndrome pathology
- Abstract
Aniridia usually occurs in isolation, but may also occur as part of the WAGR contiguous gene deletion syndrome, which includes Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation. The aniridia and predisposition for Wilms tumor seen in WAGR are caused by haploinsufficiency for PAX 6 and WT1, respectively. We present a female infant with aniridia, bilateral ptosis, bilateral posterior capsular cataracts, nystagmus, left-sided glaucoma, microcephaly, mild unilateral hydronephrosis, poor linear growth, and gross motor delay consistent with a clinical diagnosis of WAGR syndrome. In addition, weight-for-height ratio at 12 months is at the 94th centile, raising the possibility of a diagnosis of WAGRO (WAGR + Obesity). Chromosome analysis revealed a translocation (11;15)(p13;p11.2) which has not been previously associated with a diagnosis of WAGR. Subsequent clinical WAGR fluorescent in situ hybridization (FISH) analysis demonstrated a deletion of 11p13 including PAX6 and WT1. A complete FISH-mapping of the breakpoints on chromosome 11 revealed a 7 Mb deletion within 11p13-11p14. The patient is examined in light of other reported patients with deletions and/or translocations involving the regions between 11p12 --> 11p14 including patients with WAGR + obesity (WAGRO) as well as with other reported patients with aniridia and congenital ptosis., (Copyright 2006 Wiley-Liss, Inc.)
- Published
- 2006
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30. Cryptic unbalanced translocation t(17;18)(p13.2;q22.3) identified by subtelomeric FISH and defined by array-based comparative genomic hybridization in a patient with mental retardation and dysmorphic features.
- Author
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Hwang KS, Pearson MA, Stankiewicz P, Lennon PA, Cooper ML, Wu J, Ou Z, Cai WW, Patel A, and Cheung SW
- Subjects
- Abnormalities, Multiple pathology, Child, Preschool, Chromosome Banding, Female, Genome, Human, Humans, In Situ Hybridization, Fluorescence methods, Karyotyping, Nucleic Acid Hybridization methods, Syndrome, Telomere genetics, Abnormalities, Multiple genetics, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 18 genetics, Face abnormalities, Intellectual Disability pathology, Translocation, Genetic
- Abstract
Molecular cytogenetics allows the identification of cryptic chromosome rearrangements, which is clinically useful in mentally retarded and/or dysmorphic individuals with normal results from conventional cytogenetics analysis. We report on a 3-year-old girl with mental retardation, growth deficiency, speech delay, and dysmorphic features including hypertelorism, upslanting palpebral fissures, midfacial hypoplasia, and posteriorly rotated ears. The G-banding analysis showed a 46,XX,t(3;8)(q26.2;p21.1)mat karyotype. However, her clinical features were suggestive of the 18q syndrome. Subtelomeric FISH analysis revealed a der(18) translocated material from chromosome 17. Array-based comparative genomic hybridization (array-CGH) with subtelomeric BAC and PAC clones confirmed the abnormality and refined the breakpoints to 18q22.3-qter and 17p13.2-pter (deletion of 8.5 Mb and duplication of 3.9 Mb, respectively). This case demonstrates the diagnostic utility of combining conventional cytogenetics with molecular chromosome analyses for the identification of subtle chromosome abnormalities., (Copyright 2005 Wiley-Liss, Inc.)
- Published
- 2005
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31. Web enabling technology for the design, enumeration, optimization and tracking of compound libraries.
- Author
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Feuston BP, Chakravorty SJ, Conway JF, Culberson JC, Forbes J, Kraker B, Lennon PA, Lindsley C, McGaughey GB, Mosley R, Sheridan RP, Valenciano M, and Kearsley SK
- Subjects
- Molecular Structure, Combinatorial Chemistry Techniques, Computer-Aided Design, Databases, Factual, Internet, Libraries, Digital
- Abstract
Motivated by the need to augment Merck's in-house small molecule collection, web-based tools for designing, enumerating, optimizing and tracking compound libraries have been developed. The path leading to the current version of this Virtual Library Tool Kit (VLTK) is discussed in context of the (then) available commercial offerings and the constraints and requirements imposed by the end users. Though the effort was initiated to simplify the tasks of designing novel, drug-like and diverse compound libraries containing between 2K-10K unique entities, it has also evolved into a powerful tool for outsourcing syntheses as well as lead identification and optimization. The web tool includes components that select reagents, analyze synthons, identify backup reagents, enumerate libraries, calculate properties, optimize libraries and finally track the synthesized compounds through biological assays. In addition to accommodating project specific designs and virtual 3D library scanning, the application includes tools for parallel synthesis, laboratory automation and compound registration.
- Published
- 2005
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32. Interactive computer technology for skin cancer prevention targeting children.
- Author
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Hornung RL, Lennon PA, Garrett JM, DeVellis RF, Weinberg PD, and Strecher VJ
- Subjects
- Analysis of Variance, CD-ROM, Child, Female, Health Knowledge, Attitudes, Practice, Humans, Male, Multimedia, North Carolina, Skin Pigmentation, User-Computer Interface, Computer-Assisted Instruction, Health Education methods, Skin Neoplasms prevention & control
- Abstract
Background: Computer technology has become an integral part of health care, yet there have been few studies exploring the use of multimedia technology in the prevention of cancer, especially targeting children., Objective: The aims of this study were to develop and evaluate a new multimedia computer program for the primary prevention of skin cancer among a childhood population., Design and Participants: An interactive CD-ROM program was developed, then pilot tested in a public elementary school in rural North Carolina. This intervention trial involved 8 third- and fourth-grade classes (N = 209 students), randomized into 3 groups: computer intervention, standard teacher-led intervention, and controls., Main Outcome Measures: Students were tested using pre- and postintervention surveys that measured knowledge, attitudes, and self-reported behaviors. A 7-month follow-up survey was performed., Results: There was a significant increase in postintervention knowledge for the computer group when compared to either the teacher-led or control groups (mean scores out of 100: 75.2, 59.5, 55.0, respectively; p < 0.001). Attitudes about suntanning demonstrated a significant difference between the 3 groups (mean scores out of 100: 64.0, 53.0, 48.6, respectively; p = 0.002). There were slight improvements in the behavioral scores, especially among the computer group, but the overall differences were not significant. Similar overall results were found for the long-term follow-up survey, except that attitudes about suntanning no longer demonstrated a significant difference., Conclusion: These results indicate that this new educational tool is an effective way to introduce health education programs for young children in typical classroom settings. This prototype may serve as a model for the development of future preventive school-based programs, including applications to other conditions associated with high-risk behaviors among children.
- Published
- 2000
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33. Ribosomal DNA internal transcribed spacer analysis supports synonomy of Scedosporium inflatum and Lomentospora prolificans.
- Author
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Lennon PA, Cooper CR Jr, Salkin IF, and Lee SB
- Subjects
- Base Sequence, Mitosporic Fungi classification, Molecular Sequence Data, Polymerase Chain Reaction, Polymorphism, Restriction Fragment Length, DNA, Fungal genetics, DNA, Ribosomal genetics, Mitosporic Fungi genetics
- Abstract
Scedosporium inflatum is a dematiaceous opportunistic pathogen originally described by D. Malloch and I.F. Salkin (Mycotaxon 21:247-255, 1984). However, E. Gueho and G. S. De Hoog (J. Mycol. Med. 118:3-9, 1991) recently suggested reducing this mold to synonomy with Lomentospora prolificans on the basis of their similar morphological and molecular characteristics. We have investigated the ribosomal DNA internal transcribed spacers (ITS), i.e., ITS I and ITS II, of 18 isolates, including these two fungi and a closely related pathogen, Scedosporium apiospermum, and its telemorph, Pseudallescheria boydii. Identical ITS restriction fragment length polymorphisms were found in eight isolates of S. inflatum and L. prolificans. These results support Gueho and De Hoog's proposal to combine S. inflatum and L. prolificans into the binomial Scedosporium prolificans. However, the ITS I sequence of S. apiospermum and the ITS restriction fragment length polymorphisms of S. apiospermum and P. boydii were found to be significantly different from those of S. inflatum and L. prolificans. The ITS restriction pattern differences may be valuable in clinical settings for distinguishing these fungi.
- Published
- 1994
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34. Treatment of smoke inhalation by hyperbaric oxygen.
- Author
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Hart GB, Strauss MB, Lennon PA, and Whitcraft DD 3rd
- Subjects
- Adult, Aged, Ampicillin therapeutic use, Burns, Inhalation blood, Burns, Inhalation drug therapy, Cephalosporins therapeutic use, Child, Preschool, Cyanides poisoning, Electrocardiography, Female, Humans, Infant, Male, Monitoring, Physiologic, Pneumonia prevention & control, Prospective Studies, Steroids therapeutic use, Burns, Inhalation therapy, Hyperbaric Oxygenation
- Abstract
Five patients with smoke inhalation from house fires presented to the hospital in a comatose state. Carboxyhemoglobin levels were elevated in all five patients, mean=32% +/- 6. Arterial blood gases revealed the following means: pH 7.16 +/- 0.06; PCO2 35 mm HG +/- 10.5; HCO3 12.6 mEq/L +/- 0.07; base excess -16 mEq/L +/- 1.58; PO2 353 mm Hg +/- 149; O2 saturation 66% +/- 5.5. The patients were presumed to have both cyanide and carbon monoxide intoxication and were treated with the cyanide antidote kit and hyperbaric oxygen (HBO). Four of five patients awoke within 15 minutes of reaching maximum pressure and remained neurologically intact thereafter. The fifth patient died one week later. Cyanide blood levels drawn prior to treatment revealed a mean of 1.62 microgram/mL +/- 1.44. The highest cyanide level was 3.9 microgram/mL (the death) and the lowest 0.35 microgram/mL. We conclude that smoke inhalation can result in acute cyanide poisoning and that hyperbaric oxygen is a useful adjunct in the treatment of smoke inhalation.
- Published
- 1985
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- View/download PDF
35. Transient blindness associated with renal failure.
- Author
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Lennon PA, Adam WR, Bladin P, Coote BD, Dawborn JK, and Greer CH
- Subjects
- Adult, Aged, Body Weight, Brain Edema complications, Creatinine blood, Electroencephalography, Female, Hemoglobins, Humans, Hypertension, Renal complications, Lupus Erythematosus, Systemic complications, Middle Aged, Myocardial Infarction complications, Renal Dialysis, Retina pathology, Retinal Detachment complications, Retinal Detachment pathology, Sodium blood, Urea blood, Visual Fields, Water-Electrolyte Balance, Blindness etiology, Kidney Failure, Chronic complications
- Published
- 1971
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