48 results on '"Goodman BK"'
Search Results
2. Myeloid neoplasms secondary to plasma cell myeloma: an intrinsic predisposition or therapy-related phenomenon?: a clinicopathologic study of 41 cases and correlation of cytogenetic features with treatment regimens.
- Author
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Reddi DM, Lu CM, Fedoriw G, Liu YC, Wang FF, Ely S, Boswell EL, Louissaint A Jr, Arcasoy MO, Goodman BK, and Wang E
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- 2012
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3. Pelger-Huët anomaly in a child with 1q42.3-44 deletion.
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Kalfa TA, Zimmerman SA, Goodman BK, McDonald MT, and Ware RE
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- 2006
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4. Morphologic examination of sequential bone marrow biopsies after nonmyeloablative stem cell transplantation complements molecular studies of donor engraftment.
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Lagoo AS, Gong JZ, Stenzel TT, Goodman BK, Buckley PJ, Chao NJ, Gasparetto C, Long GD, and Rizzieri DA
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- 2006
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5. The value of fluorescence in situ hybridization and polymerase chain reaction in the diagnosis of B-cell non-Hodgkin lymphoma by fine-needle aspiration.
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Safley AM, Buckley PJ, Creager AJ, Dash RC, Dodd LG, Goodman BK, Jones CK, Lagoo AS, Stenzel TT, Wang W, Xie B, and Gong JZ
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- 2004
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6. MLL duplication in a pediatric patient with B-cell lymphoblastic lymphoma.
- Author
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Mater DV, Goodman BK, Wang E, Gaca AM, and Wechsler DS
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- Child, Cytogenetic Analysis, Flow Cytometry, Histone-Lysine N-Methyltransferase, Humans, Male, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Tomography, X-Ray Computed, Gene Duplication, Myeloid-Lymphoid Leukemia Protein genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Lymphoblastic lymphoma is the second most common type of non-Hodgkin lymphoma seen in children. Approximately, 90% of lymphoblastic lymphomas arise from T cells, with the remaining 10% being B-cell-lineage derived. Although T-cell lymphoblastic lymphoma most frequently occurs in the anterior mediastinum (thymus), B-cell lymphoblastic lymphoma (B-LBL) predominates in extranodal sites such as skin and bone. Here, we describe a pediatric B-LBL patient who presented with extensive abdominal involvement and whose lymphoma cells displayed segmental duplication of the mixed lineage leukemia (MLL) gene. MLL duplication/amplification has been described primarily in acute myeloid leukemia and myelodysplastic syndrome with no published reports of discrete MLL duplication/amplification events in B-LBL. The MLL gene duplication noted in this case may represent a novel mechanism for tumorigenesis in B-LBL.
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- 2012
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7. SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target.
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Christensen DJ, Chen Y, Oddo J, Matta KM, Neil J, Davis ED, Volkheimer AD, Lanasa MC, Friedman DR, Goodman BK, Gockerman JP, Diehl LF, de Castro CM, Moore JO, Vitek MP, and Weinberg JB
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- Animals, Cell Line, Tumor, DNA-Binding Proteins, Humans, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Lymphoma, Non-Hodgkin metabolism, Lymphoma, Non-Hodgkin pathology, Male, Mice, Mice, SCID, Myeloid Cell Leukemia Sequence 1 Protein, Protein Phosphatase 2 metabolism, Proto-Oncogene Proteins c-bcl-2 biosynthesis, Xenograft Model Antitumor Assays, Gene Expression Regulation, Leukemic drug effects, Histone Chaperones agonists, Histone Chaperones biosynthesis, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Lymphoma, Non-Hodgkin drug therapy, Peptides pharmacology, Transcription Factors agonists, Transcription Factors biosynthesis
- Abstract
B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL.
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- 2011
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8. College of American Pathologists/American College of Medical Genetics proficiency testing for constitutional cytogenomic microarray analysis.
- Author
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Brothman AR, Dolan MM, Goodman BK, Park JP, Persons DL, Saxe DF, Tepperberg JH, Tsuchiya KD, Van Dyke DL, Wilson KS, Wolff DJ, and Theil KS
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- Cytogenetic Analysis methods, Data Collection, Humans, Laboratories standards, Microarray Analysis methods, Societies, Medical, United States, Cytogenetic Analysis standards, Laboratory Proficiency Testing standards, Microarray Analysis standards
- Abstract
Purpose: To evaluate the feasibility of administering a newly established proficiency test offered through the College of American Pathologists and the American College of Medical Genetics for genomic copy number assessment by microarray analysis, and to determine the reproducibility and concordance among laboratory results from this test., Methods: Surveys were designed through the Cytogenetic Resource Committee of the two colleges to assess the ability of testing laboratories to process DNA samples provided and interpret results. Supplemental questions were asked with each Survey to determine laboratory practice trends., Results: Twelve DNA specimens, representing 2 pilot and 10 Survey challenges, were distributed to as many as 74 different laboratories, yielding 493 individual responses. The mean consensus for matching result interpretations was 95.7%. Responses to supplemental questions indicate that the number of laboratories offering this testing is increasing, methods for analysis and evaluation are becoming standardized, and array platforms used are increasing in probe density., Conclusion: The College of American Pathologists/American College of Medical Genetics proficiency testing program for copy number assessment by cytogenomic microarray is a successful and efficient mechanism for assessing interlaboratory reproducibility. This will provide laboratories the opportunity to evaluate their performance and assure overall accuracy of patient results. The high level of concordance in laboratory responses across all testing platforms by multiple facilities highlights the robustness of this technology.
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- 2011
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9. Immunophenotypic and gene expression analysis of monoclonal B-cell lymphocytosis shows biologic characteristics associated with good prognosis CLL.
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Lanasa MC, Allgood SD, Slager SL, Dave SS, Love C, Marti GE, Kay NE, Hanson CA, Rabe KG, Achenbach SJ, Goldin LR, Camp NJ, Goodman BK, Vachon CM, Spector LG, Rassenti LZ, Leis JF, Gockerman JP, Strom SS, Call TG, Glenn M, Cerhan JR, Levesque MC, Weinberg JB, and Caporaso NE
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- Biomarkers, Tumor metabolism, Flow Cytometry, Humans, Immunophenotyping, In Situ Hybridization, Fluorescence, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Oligonucleotide Array Sequence Analysis, Prognosis, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, B-Lymphocytes pathology, Biomarkers, Tumor genetics, Gene Expression Profiling, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Lymphocytosis pathology
- Abstract
Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and 'CLL-like' MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.
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- 2011
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10. Donor cell leukemia in umbilical cord blood transplant patients: a case study and literature review highlighting the importance of molecular engraftment analysis.
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Crow J, Youens K, Michalowski S, Perrine G, Emhart C, Johnson F, Gerling A, Kurtzberg J, Goodman BK, Sebastian S, Rehder CW, and Datto MB
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- Bone Marrow Transplantation, Child, Preschool, Female, Humans, Immunophenotyping, Infant, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Recurrence, Cord Blood Stem Cell Transplantation, Leukemia, Myeloid, Acute pathology, Neoplasm Transplantation adverse effects, Tissue Donors
- Abstract
Donor cell neoplasms are rare complications of treatment regimens that involve stem cell transplantation for hematological malignancies, myelodysplastic processes, or certain genetic or metabolic disorders. We report a case of donor cell leukemia in a pediatric patient with a history of acute myeloid leukemia that manifested as recurrent AML FAB type M5 fourteen months after umbilical cord blood transplantation. Although there was some immunophenotypic drift from the patient's original AML and their posttransplant presentation, the initial pathological impression was of recurrent disease. Bone marrow engraftment analysis by multiplex PCR of short tandem repeat markers performed on the patient's diagnostic specimen showed complete engraftment by donor cells, with a loss of heterozygosity in the donor alleles on chromosome 7. This led to the reinterpretation of this patient's disease as donor-derived leukemia. This interpretation was supported by a routine karyotype and fluorescence in situ hybridization analysis showing loss of chromosome 7 and a male (donor) chromosome complement in this female patient. Also noted was a loss of the patient's presenting chromosomal abnormality, t(11;19)(q23;p13). This case highlights the need for close coordination between all aspects of clinical testing for the transplant patient, including molecular engraftment studies, when distinguishing the very common complication of recurrent disease from the exceedingly rare complication of donor cell leukemia.
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- 2010
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11. A single tube, four-color flow cytometry assay for evaluation of ZAP-70 and CD38 expression in chronic lymphocytic leukemia.
- Author
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Hassanein NM, Perkinson KR, Alcancia F, Goodman BK, Weinberg JB, and Lagoo AS
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- ADP-ribosyl Cyclase 1 genetics, Biomarkers, Tumor blood, Chromosome Aberrations, DNA Mutational Analysis, DNA, Neoplasm analysis, Gene Expression Regulation, Humans, Immunoglobulin Heavy Chains blood, Immunoglobulin Heavy Chains genetics, Immunoglobulin Variable Region genetics, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Membrane Glycoproteins genetics, Neoplasm Staging, Predictive Value of Tests, Prognosis, ZAP-70 Protein-Tyrosine Kinase genetics, ADP-ribosyl Cyclase 1 blood, Flow Cytometry methods, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Membrane Glycoproteins blood, ZAP-70 Protein-Tyrosine Kinase blood
- Abstract
We describe a simple and robust flow cytometry assay for ZAP-70 and CD38 expression. The steps required to validate this assay in a clinical flow cytometry laboratory are described. Two criteria were used to characterize ZAP-70 expression into positive, negative, and indeterminate categories and applied to 111 cases of chronic lymphocytic leukemia (CLL) resulting in 29.7% positive, 56.8% negative, and 13.5% indeterminate cases. A sensitivity-specificity crossover plot between ZAP-70 and CD38 suggested a cutoff of 12.5% for defining CD38 positivity. ZAP-70+ cases were significantly more likely to be at a higher clinical stage and, together with CD38+ cases, were more likely to have unmutated IgV(H). However, for individual patients, the concordance between these markers was not perfect. It may be necessary to evaluate several prognostic markers simultaneously in CLL, and availability of convenient assays for ZAP-70 and CD38 is desirable for optimal clinical decision making.
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- 2010
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12. Single-cell analysis reveals oligoclonality among 'low-count' monoclonal B-cell lymphocytosis.
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Lanasa MC, Allgood SD, Volkheimer AD, Gockerman JP, Whitesides JF, Goodman BK, Moore JO, Weinberg JB, and Levesque MC
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- Aged, Aged, 80 and over, Chromosome Aberrations, Female, Genes, Immunoglobulin, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Variable Region genetics, Immunophenotyping, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphocytosis genetics, Male, Middle Aged, B-Lymphocytes pathology, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Lymphocytosis immunology
- Abstract
Monoclonal B-cell lymphocytosis (MBL) is a preclinical hematologic syndrome characterized by small accumulations of CD5(+) B lymphocytes. Most MBL share phenotypic characteristics with chronic lymphocytic leukemia (CLL). Although some MBL progress to CLL, most MBL have apparently limited potential for progression to CLL, particularly those MBL with normal absolute B-cell counts ('low-count' MBL). Most CLL are monoclonal and it is not known whether MBL are monoclonal or oligoclonal; this is important because it is unclear whether MBL represent indolent CLL or represent a distinct premalignant precursor before the development of CLL. We used flow cytometry analysis and sorting to determine immunophenotypic characteristics, clonality and molecular features of MBL from familial CLL kindreds. Single-cell analysis indicated four of six low-count MBL consisted of two or more unrelated clones; the other two MBL were monoclonal. 87% of low-count MBL clones had mutated immunoglobulin genes, and no immunoglobulin heavy-chain rearrangements of V(H) family 1 were observed. Some MBL were diversified, clonally related populations with evidence of antigen drive. We conclude that although low-count MBL share many phenotypic characteristics with CLL, many MBL are oligoclonal. This supports a model for step-wise development of MBL into CLL.
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- 2010
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13. A genomic approach to improve prognosis and predict therapeutic response in chronic lymphocytic leukemia.
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Friedman DR, Weinberg JB, Barry WT, Goodman BK, Volkheimer AD, Bond KM, Chen Y, Jiang N, Moore JO, Gockerman JP, Diehl LF, Decastro CM, Potti A, and Nevins JR
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- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Agents pharmacology, Chlorambucil pharmacology, Cyclophosphamide pharmacology, Disease Progression, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genomics methods, Humans, Immunotherapy methods, Male, Middle Aged, Pentostatin pharmacology, Pharmacogenetics methods, Prognosis, Risk, Rituximab, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell therapy
- Abstract
Purpose: Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a variable clinical course. Several parameters have prognostic capabilities but are associated with altered response to therapy in only a small subset of patients., Experimental Design: We used gene expression profiling methods to generate predictors of therapy response and prognosis. Genomic signatures that reflect progressive disease and responses to chemotherapy or chemoimmunotherapy were created using cancer cell lines and patient leukemia cell samples. We validated and applied these three signatures to independent clinical data from four cohorts, representing a total of 301 CLL patients., Results: A genomic signature of prognosis created from patient leukemic cell gene expression data coupled with clinical parameters significantly differentiated patients with stable disease from those with progressive disease in the training data set. The progression signature was validated in two independent data sets, showing a capacity to accurately identify patients at risk for progressive disease. In addition, genomic signatures that predict response to chlorambucil or pentostatin, cyclophosphamide, and rituximab were generated and could accurately distinguish responding and nonresponding CLL patients., Conclusions: Thus, microarray analysis of CLL lymphocytes can be used to refine prognosis and predict response to different therapies. These results have implications for standard and investigational therapeutics in CLL patients.
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- 2009
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14. Reduced ATR or Chk1 expression leads to chromosome instability and chemosensitization of mismatch repair-deficient colorectal cancer cells.
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Jardim MJ, Wang Q, Furumai R, Wakeman T, Goodman BK, and Wang XF
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- Animals, Antimetabolites, Antineoplastic therapeutic use, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins genetics, Cell Line, Tumor, Centrosome metabolism, Checkpoint Kinase 1, Colorectal Neoplasms drug therapy, DNA Breaks, Double-Stranded, Fluorouracil therapeutic use, Humans, Protein Kinases genetics, Protein Serine-Threonine Kinases genetics, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Cell Cycle Proteins metabolism, Chromosomal Instability, Colorectal Neoplasms genetics, DNA Mismatch Repair, Protein Kinases metabolism, Protein Serine-Threonine Kinases metabolism
- Abstract
Genomic instability in colorectal cancer is categorized into two distinct classes: chromosome instability (CIN) and microsatellite instability (MSI). MSI is the result of mutations in the mismatch repair (MMR) machinery, whereas CIN is often thought to be associated with a disruption in the APC gene. Clinical data has recently shown the presence of heterozygous mutations in ATR and Chk1 in human cancers that exhibit MSI, suggesting that those mutations may contribute to tumorigenesis. To determine whether reduced activity in the DNA damage checkpoint pathway would cooperate with MMR deficiency to induce CIN, we used siRNA strategies to partially decrease the expression of ATR or Chk1 in MMR-deficient colorectal cancer cells. The resultant cancer cells display a typical CIN phenotype, as characterized by an increase in the number of chromosomal abnormalities. Importantly, restoration of MMR proficiency completely inhibited induction of the CIN phenotype, indicating that the combination of partial checkpoint blockage and MMR deficiency is necessary to trigger CIN. Moreover, disruption of ATR and Chk1 in MMR-deficient cells enhanced the sensitivity to treatment with the commonly used colorectal chemotherapeutic compound, 5-fluorouracil. These results provide a basis for the development of a combination therapy for those cancer patients.
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- 2009
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15. Clinicopathologic findings in high-grade B-cell lymphomas with typical Burkitt morphologic features but lacking the MYC translocation.
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Sevilla DW, Gong JZ, Goodman BK, Buckley PJ, Rosoff P, Gockerman JP, and Lagoo AS
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- Adolescent, Adult, Aged, Antigens, CD20 metabolism, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor metabolism, Burkitt Lymphoma drug therapy, Burkitt Lymphoma metabolism, Cell Proliferation, Child, Child, Preschool, Disease-Free Survival, Female, Humans, Immunophenotyping, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse metabolism, Male, Middle Aged, Neprilysin metabolism, Treatment Outcome, Burkitt Lymphoma diagnosis, Burkitt Lymphoma genetics, Genes, myc, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse genetics, Translocation, Genetic
- Abstract
In the World Health Organization classification, cases with classical Burkitt morphologic features and a very high proliferation fraction but without the MYC translocation are not clearly designated as a separate entity and are usually categorized as diffuse large B-cell lymphoma (DLBCL). We identified from our records 33 cases of highly aggressive mature B-cell neoplasms from 8 children and 25 adults with typical Burkitt cytomorphologic, histologic, and immunophenotypic (CD20+/CD10+ and surface immunoglobulin-positive) features. Rearrangement of MYC (MYC+) was present in only 18 of 33 cases, but the proliferation fraction was more than 90% in all MYC-cases (no MYC rearrangement). The immunophenotype of the lymphoma cells in the 2 groups was similar. Although children with MYC+ and MYC- neoplasms were treated with chemotherapy regimens appropriate for Burkitt lymphoma, adults with MYC- lymphomas received less aggressive therapy usually given for DLBCL. Survival analysis showed that adults in the MYC- group had an inferior outcome compared with adults with MYC+ disease. Provisional identification of MYC- lymphomas with typical Burkitt morphologic features as an entity separate from DLBCL will facilitate further studies and possible categorization as a separate entity.
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- 2007
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16. Clinical and molecular predictors of disease severity and survival in chronic lymphocytic leukemia.
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Weinberg JB, Volkheimer AD, Chen Y, Beasley BE, Jiang N, Lanasa MC, Friedman D, Vaccaro G, Rehder CW, Decastro CM, Rizzieri DA, Diehl LF, Gockerman JP, Moore JO, Goodman BK, and Levesque MC
- Subjects
- ADP-ribosyl Cyclase 1 genetics, Age of Onset, Aged, Female, Follow-Up Studies, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Variable Region genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Neoplasm Staging, Severity of Illness Index, Survival Analysis, Time Factors, Virginia, ZAP-70 Protein-Tyrosine Kinase genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell physiopathology
- Abstract
Several parameters may predict disease severity and overall survival in chronic lymphocytic leukemia (CLL). The purpose of our study of 190 CLL patients was to compare immunoglobulin heavy chain variable region (IgV(H)) mutation status, cytogenetic abnormalities, and leukemia cell CD38 and Zap-70 to older, traditional parameters. We also wanted to construct a simple, inexpensive prognosis score that would significantly predict TTT and survival in patients at the time of diagnosis and help practicing clinicians. In univariate analyses, patients with higher clinical stage, higher leukocyte count at diagnosis, shorter leukocyte doubling time, elevated serum lactate dehydrogenase (LDH), unmutated immunoglobulin heavy chain variable region (IgV(H)) genes, and higher CD38 had a shorter overall survival and time-to-treatment (TTT). CLL cell Zap-70 expression was higher in patients with unmutated IgV(H), and those with higher Zap-70 tended to have shorter survival. IgV(H)4-34 or IgV(H)1-69 was the most common IgV(H) genes used (16 and 12%, respectively). Of those with IgV(H)1-69, 86% had unmutated IgV(H) and had a significantly shorter TTT. A cytogenetic abnormality was noted in 71% of the patients tested. Patients with 11q22 del and 17p13 del or complex abnormalities were significantly more likely to have unmutated IgV(H). We found that a prognostic score constructed using modified Rai stage, cellular CD38, and serum LDH (parameters easily obtained clinically) significantly predicted TTT and survival in patients at the time of diagnosis and performed as well or better than models using the newer markers.
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- 2007
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17. Progressive immunoglobulin gene mutations in chronic lymphocytic leukemia: evidence for antigen-driven intraclonal diversification.
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Volkheimer AD, Weinberg JB, Beasley BE, Whitesides JF, Gockerman JP, Moore JO, Kelsoe G, Goodman BK, and Levesque MC
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- Aged, Clone Cells immunology, Female, Humans, Immunoglobulin Heavy Chains, Immunoglobulin Light Chains, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Receptors, Fc, Antigens physiology, Genes, Immunoglobulin genetics, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Mutation
- Abstract
Somatic mutations of immunoglobulin genes characterize mature memory B cells, and intraclonal B-cell diversification is typically associated with expansion of B-cell clones with greater affinity for antigen (antigen drive). Evidence for a role of antigen in progression of intraclonal chronic lymphocytic leukemia (CLL) cell diversification in patients with mutated immunoglobulin genes has not been previously presented. We performed a single-cell analysis of immunoglobulin heavy and light chains in 6 patients with somatically mutated CLL-cell immunoglobulin genes and identified 2 patients with multiple related (oligoclonal) subgroups of CLL cells. We constructed genealogic trees of these oligoclonal CLL-cell subgroups and assessed the effects of immunoglobulin somatic mutations on the ratios of replacement and silent amino acid changes in the framework and antigen-binding regions (CDRs) of the immunoglobulin heavy and light chains from each oligoclonal CLL-cell population. In one subject, the amino acid changes were consistent with an antigen-driven progression of clonally related CLL-cell populations. In the other subject, intraclonal diversification was associated with immunoglobulin amino acid changes that would have likely lessened antigen affinity. Taken together, these studies support the hypothesis that in some CLL cases intraclonal diversification is dependent on antigen interactions with immunoglobulin receptors.
- Published
- 2007
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18. Genetically characterized positive control cell lines derived from residual clinical blood samples.
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Bernacki SH, Beck JC, Stankovic AK, Williams LO, Amos J, Snow-Bailey K, Farkas DH, Friez MJ, Hantash FM, Matteson KJ, Monaghan KG, Muralidharan K, Pratt VM, Prior TW, Richie KL, Levin BC, Rohlfs EM, Schaefer FV, Shrimpton AE, Spector EB, Stolle CA, Strom CM, Thibodeau SN, Cole EC, Goodman BK, and Stenzel TT
- Subjects
- Genetic Diseases, Inborn diagnosis, Humans, Laboratories, Molecular Biology, Mutation, Point Mutation, Sequence Deletion, Blood Specimen Collection, Cell Line, Transformed, Genetic Testing methods, Herpesvirus 4, Human, Lymphocytes cytology
- Abstract
Background: Positive control materials for clinical diagnostic molecular genetic testing are in critically short supply. High-quality DNA that closely resembles DNA isolated from patient specimens can be obtained from Epstein-Barr virus (EBV)-transformed peripheral blood lymphocyte cell lines. Here we report the development of a process to (a) recover residual blood samples with clinically important mutations detected during routine medical care, (b) select samples likely to provide viable lymphocytes for EBV transformation, (c) establish stable cell lines and confirm the reported mutation(s), and (d) validate the cell lines for use as positive controls in clinical molecular genetic testing applications., Methods: A network of 32 genetic testing laboratories was established to obtain anonymous, residual clinical samples for transformation and to validate resulting cell lines for use as positive controls. Three panel meetings with experts in molecular genetic testing were held to evaluate results and formulate a process that could function in the context of current common practices in molecular diagnostic testing., Results: Thirteen laboratories submitted a total of 113 residual clinical blood samples with mutations for 14 genetic disorders. Forty-one EBV-transformed cell lines were established. Thirty-five individual point and deletion mutations were shown to be stable after 20 population doublings in culture. Thirty-three cell lines were characterized for specific mutations and validated for use as positive controls in clinical diagnostic applications., Conclusions: A process for producing and validating positive control cell lines from residual clinical blood samples has been developed. Sustainable implementation of the process could help alleviate the current shortage of positive control materials.
- Published
- 2005
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19. Triploid mosaicism in a 45,X/69,XXY infant.
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Quigley DI, McDonald MT, Krishnamuthy V, Kishnani PS, Lee MM, Haqq AM, and Goodman BK
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- Abnormalities, Multiple pathology, Fingers abnormalities, Genitalia, Male abnormalities, Humans, In Situ Hybridization, Fluorescence, Infant, Karyotyping, Male, Abnormalities, Multiple genetics, Aneuploidy, Mosaicism, Sex Chromosome Aberrations
- Abstract
We report on an infant referred for chromosome analysis during the neonatal period due to ambiguous genitalia. The genitalia appeared male with bilaterally palpable testes, penoscrotal hypospadias, chordee, and a bifid scrotum. Chromosome analysis and interphase FISH analysis of lymphocytes showed a 45,X karyotype and no evidence for SRY in 200 nuclei examined, respectively. Subsequent chromosome analysis of fibroblasts revealed a 69,XXY karyotype. Molecular studies were carried out to determine the etiology of the chromosome findings. Results indicated that the two cell lines are mosaic rather than chimeric and that the triploidy resulted from delayed dispermy rather than delayed polar body inclusion. To our knowledge this is the first reported living individual with (near) diploid/triploid mosaicism for 45,X/69,XXY., ((c) 2005 Wiley-Liss, Inc.)
- Published
- 2005
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20. Loss of chromosome 13 in a case of soft tissue perineurioma.
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Mott RT, Goodman BK, Burchette JL, and Cummings TJ
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- Adult, Female, Humans, Nerve Sheath Neoplasms metabolism, Nerve Sheath Neoplasms pathology, Soft Tissue Neoplasms metabolism, Soft Tissue Neoplasms pathology, Chromosome Deletion, Chromosomes, Human, Pair 13 genetics, Nerve Sheath Neoplasms genetics, Soft Tissue Neoplasms genetics, Thigh
- Abstract
Soft tissue perineuriomas are rare mesenchymal tumors that are derived from perineurial cells of the peripheral nerve sheath. Although the histological and immunohistochemical features of soft tissue perineuriomas are well described, little is known regarding the cytogenetic abnormalities in these tumors. Herein, we describe a case of a large (12.2 cm) soft tissue perineurioma that arose in the thigh of a 26-year-old Caucasian female. Histologically, the tumor was composed of a diffuse to fascicular arrangement of spindle cells with bland, elongated nuclei with long, thin, tapering cytoplasmic processes. The immunohistochemical profile was consistent with a perineurial cell origin with expression of epithelial membrane antigen, vimentin, and collagen type IV. Cytogenetic evaluation revealed loss of chromosome 13 as the sole abnormality in the majority of examined cells. In contrast to previous reports, we were unable to demonstrate deletion or structural abnormalities of chromosome 22 by either fluorescence in situ hybridization (FISH) or metaphase cytogenetics. This is the first report of loss of chromosome 13 in soft tissue perineurioma. Although never described in this group of neoplasms, loss of chromosome 13 has been identified in a large number of other soft tissue tumors, particularly sarcomas and malignant peripheral nerve sheath tumors. Herein, we discuss this case and provide a review of the literature.
- Published
- 2005
21. Molecular and cytogenetic characterization of a novel rearrangement involving chromosomes 9, 12, and 17 resulting in ETV6 (TEL) and ABL fusion.
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Tirado CA, Sebastian S, Moore JO, Gong JZ, and Goodman BK
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- Aged, Humans, In Situ Hybridization, Fluorescence, Male, Protein-Tyrosine Kinases, Reverse Transcriptase Polymerase Chain Reaction, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 9, Oncogene Proteins, Fusion genetics, Translocation, Genetic genetics
- Abstract
We performed chromosome analysis on the bone marrow of a patient with BCR/ABL negative chronic myelogenous leukemia (CML). By interphase fluorescence in situ hybridization (FISH), an extra ABL signal was present in interphase nuclei and appeared to be located at 17p in the metaphase cells. Chromosome analysis showed a subtle abnormality at 17p13 and 12p13 but no visible rearrangement at 9q34 (ABL). Additional FISH experiments disclosed a rearrangement between the short arms of chromosomes 12 and 17 at approximately bands 12p13 and 17p13, respectively. In addition, subtelomeric FISH analysis confirmed the presence of terminal 12p at 17p13 and showed terminal 9q34 to be intact on each chromosome 9. Taken together, these results indicated a rearrangement involving chromosomes 9, 12, and 17 that suggested the possibility of juxtaposition of part of the ETV6 (also known as TEL) locus (12p13) with a portion of ABL (9q34) together at 17p13. The ETV6/ABL fusion was confirmed by RT-PCR, which showed that the first 5 exons of ETV6 were fused in frame with ABL at exon 2. Wild-type ETV6 and ABL were also expressed, in accordance with the FISH results that showed no loss of the second ETV6 or ABL allele.
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- 2005
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22. A case of infantile acute lymphoblastic leukemia presenting with rearrangement of MLL at 11q23 and apparent insertion or translocation at 10p12.
- Author
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Tirado CA, Lager J, Rosoff PM, Golembiski-Ruiz V, Gong JZ, and Goodman BK
- Subjects
- Female, Humans, In Situ Hybridization, Fluorescence, Infant, Karyotyping, Mutation, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 11, Gene Rearrangement, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Translocation, Genetic
- Abstract
We report the case of an 11-month-old patient with a clinical diagnosis of infantile acute lymphoblastic leukemia and an MLL (11q23) rearrangement in 69% of nuclei, revealed with interphase fluorescence in situ hybridization (FISH). Routine chromosome analysis of the bone marrow showed a very subtle rearrangement involving the short arm of chromosome 10 and the long arm of chromosome 11 in the abnormal cells. To clarify the nature of this rearrangement, we hybridized the MLL break-apart probe to previously G-banded slides. The rearrangement was interpreted as a small inversion within the band 11q23, separating the 5' MLL from the 3' MLL region. This segment on the long arm of chromosome 11 containing the rearranged MLL locus was either inserted in or translocated to the short arm of chromosome 10 at approximately band 10p12. The inversion affecting MLL may have followed insertion or preceded it. Molecular characterization of this rearrangement was not possible, due to limited sample material. There have been previous reports of rearrangements of MLL with the MLLT10 (alias AF10) gene locus at 10p12, including an interstitial inverted insertion of 11q13q23 in one case and insertion of 11q14q23 at 10p12 in another. These both resulted in a large derivative chromosome 10 and transcription of an MLL/MLLT10 fusion product. To our knowledge, the novel and cryptic rearrangement detected in our patient has not been described previously. A follow-up study of the patient's bone marrow at the end of induction therapy showed no morphologic evidence of residual leukemia and both FISH and chromosome analyses were normal.
- Published
- 2004
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23. ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background.
- Author
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Fang Y, Tsao CC, Goodman BK, Furumai R, Tirado CA, Abraham RT, and Wang XF
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Ataxia Telangiectasia Mutated Proteins, Carrier Proteins, Cell Cycle genetics, Cell Cycle Proteins genetics, Cell Line, Chromosomal Instability, Chromosome Aberrations, DNA genetics, DNA metabolism, Gene Amplification genetics, Genotype, Humans, Karyotyping, Mice, MutL Protein Homolog 1, Neoplasm Proteins deficiency, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Nuclear Proteins deficiency, Nuclear Proteins genetics, Nuclear Proteins metabolism, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases genetics, Tumor Suppressor Proteins deficiency, Tumor Suppressor Proteins genetics, Base Pair Mismatch genetics, Cell Cycle Proteins metabolism, DNA Repair genetics, Gene Dosage, Protein Serine-Threonine Kinases metabolism, Tumor Suppressor Proteins metabolism
- Abstract
The ataxia-telangiectasia mutated and rad3-related (ATR) kinase orchestrates cellular responses to DNA damage and replication stress. Complete loss of ATR function leads to chromosomal instability and cell death. However, heterozygous ATR mutations are found in human cancers with microsatellite instability, suggesting that ATR haploinsufficiency contributes to tumorigenesis. To test this possibility, we generated human cell line and mouse model systems in which a single ATR allele was inactivated on a mismatch repair (MMR)-deficient background. Monoallelic ATR gene targeting in MLH1-deficient HCT 116 colon carcinoma cells resulted in hypersensitivity to genotoxic stress accompanied by dramatic increases in fragile site instability, and chromosomal amplifications and rearrangements. The ATR(+/-) HCT 116 cells also displayed compromised activation of Chk1, an important downstream target for ATR. In complementary studies, we demonstrated that mice bearing the same Atr(+/-)/Mlh1(-/-) genotype were highly prone to both embryonic lethality and early tumor development. These results demonstrate that MMR proteins and ATR functionally interact during the cellular response to genotoxic stress, and that ATR serves as a haploinsufficient tumor suppressor in MMR-deficient cells.
- Published
- 2004
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24. Molecular and cytogenetic characterization of a novel translocation t(4;22) involving the breakpoint cluster region and platelet-derived growth factor receptor-alpha genes in a patient with atypical chronic myeloid leukemia.
- Author
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Safley AM, Sebastian S, Collins TS, Tirado CA, Stenzel TT, Gong JZ, and Goodman BK
- Subjects
- Humans, Male, Middle Aged, Myeloproliferative Disorders genetics, Oncogene Proteins, Fusion genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-bcr, Reading Frames genetics, Chromosome Breakage genetics, Chromosomes, Human, Pair 22 genetics, Chromosomes, Human, Pair 4 genetics, Cytogenetic Analysis methods, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Protein-Tyrosine Kinases, Receptor, Platelet-Derived Growth Factor alpha genetics, Translocation, Genetic genetics
- Abstract
We report a case of BCR-ABL-negative atypical chronic myeloid leukemia (CML) with translocation t(4;22) (q12;q11.2) juxtaposing the breakpoint cluster region (BCR) and platelet-derived growth factor receptor-alpha (PDGFRA) genes. The patient was a 57-year-old man with a history of stage IV diffuse large B-cell lymphoma, status post-6 cycles of combination chemotherapy in 1999, who presented in August 2002 with enlarged lymph nodes, anemia, and marked leukocytosis (50 x 10(9) g/dL) consistent with a myeloproliferative disorder (MPD). A bone marrow biopsy showed granulocytic hyperplasia, neutrophilia, and mild eosinophilia. Initial cytogenetic evaluation by interphase FISH for BCR-ABL, to rule out a translocation 9;22, showed a variant signal pattern consistent with rearrangement of BCR at 22q11.2, but not ABL at 9q34. Analysis of the patient's cDNA by polymerase chain reaction (PCR) for BCR-ABL was negative. Cytogenetic analysis showed an abnormal karyotype with rearrangement of chromosomes 4 and 22. PCR amplification and subsequent sequence analysis demonstrated an in-frame 5'-BCR/3'-PDGFRA fusion in the patient's cDNA. PDGFRA encodes a receptor tyrosine kinase and shares structural and organizational homology with the KIT and CSf1R receptor genes. However, although the incidence of MPD involving translocations of PDGFRB has been well established, to our knowledge there are only two previous reports describing a BCR-PDGFRA fusion gene, in 3 patients diagnosed with atypical CML. Here, we report the molecular and cytogenetic characterization of a patient with BCR-PDGFRA-positive MPD who had a complete hematologic response after treatment with imatinib mesylate., (Copyright 2004 Wiley-Liss, Inc.)
- Published
- 2004
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25. Increased risk for developmental delay in Saethre-Chotzen syndrome is associated with TWIST deletions: an improved strategy for TWIST mutation screening.
- Author
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Cai J, Goodman BK, Patel AS, Mulliken JB, Van Maldergem L, Hoganson GE, Paznekas WA, Ben-Neriah Z, Sheffer R, Cunningham ML, Daentl DL, and Jabs EW
- Subjects
- Base Sequence, DNA Mutational Analysis, DNA Primers, Helix-Loop-Helix Motifs, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Polymerase Chain Reaction, Reference Values, Twist-Related Protein 1, Acrocephalosyndactylia genetics, Mutation, Nuclear Proteins, Sequence Deletion genetics, Transcription Factors genetics
- Abstract
The majority of patients with Saethre-Chotzen syndrome have mutations in the TWIST gene, which codes for a basic helix-loop-helix transcription factor. Of the genetic alterations identified in TWIST, nonsense mutations, frameshifts secondary to small deletions or insertions, and large deletions implicate haploinsufficiency as the pathogenic mechanism. We identified three novel intragenic mutations and six deletions in our patients by using a new strategy to screen for TWIST mutations. We used polymerase chain reaction (PCR) amplification with subsequent sequencing to identify point mutations and small insertions or deletions in the coding region, and real-time PCR-based gene dosage analysis to identify large deletions encompassing the gene, with confirmation by microsatellite and fluorescence in situ hybridization (FISH) analyses. The size of the deletions can also be analyzed by using the gene dosage assay with "PCR walking" across the critical region. In 55 patients with features of Saethre-Chotzen syndrome, 11% were detected to have deletions by real-time gene dosage analysis. Two patients had a translocation or inversion at least 260 kb 3' of the gene, suggesting they had position-effect mutations. Of the 37 patients with classic features of Saethre-Chotzen syndrome, the overall detection rate for TWIST mutations was 68%. The risk for developmental delay in patients with deletions involving the TWIST gene is approximately 90% or eight times more common than in patients with intragenic mutations.
- Published
- 2003
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26. Cytogenetic and molecular analysis of an unusual case of acute promyelocytic leukemia with a t(15;17;17)(q22;q23;q21).
- Author
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Tirado CA, Golembiewski-Ruiz V, Horvatinovich J, Moore JO, Buckley PJ, Stenzel TT, and Goodman BK
- Subjects
- Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 17, Female, Flow Cytometry, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Middle Aged, Leukemia, Promyelocytic, Acute genetics, Translocation, Genetic
- Abstract
We present a 52-year-old female with a clinical history of acute myelocytic leukemia, probable acute promyelocytic leukemia (APL). Flow cytometry results were somewhat unusual. Specifically, the promyelocytic population showed partial positivity for antigens not usually expressed in APL (HLA-DR and CD117). The interpretation of these results was that the abnormal population contained a proportion of very early promyeolocytes that had not completely lost all their "precursor" antigens. Cytogenetic analysis of a bone marrow aspirate showed a t(15:17;17)(q22;q23;q21) in all cells analyzed. Fluorescence in situ hybridization (FISH) analysis using the PML-RARA DNA probe showed a positive signal pattern (fusion) in 100% of 200 total interphase and metaphase cells examined, confirming the presence of the PML-RARA rearrangement. Multicolor FISH, which produces 24 colors to differentiate all chromosomes in a single hybridization, was applied. This study confirmed the cytogenetic interpretation of the rearrangement. No material from any other chromosome was detected on the second smaller derivative chromosome 17. Additional studies using the RARA(17q21) break-apart DNA FISH probe showed that 17q21 (RARA) was not rearranged on the derivative chromosome 17 that received the q22-->qter segment from chromosome 15. The RARA locus on the smaller derivative 17 was the allele involved in the fusion in this three-way rearrangement. The signal pattern was consistent in 100% of interphase and metaphase cells scored. This unusual t(15;17;17) prompted us to investigate further using reverse-transcription polymerase chain reaction with primers from the 3' and 5' regions of both the RARA and PML loci. These studies showed that the PML-RARA fusion was present, but the complementary fusion RARA-PML, which is usually detectable, was absent. The patient is responding well to standard treatment protocols.
- Published
- 2003
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27. Molecular cytogenetic characterization of a subtle interstitial del(3)(p25.3p26.2) in a patient with deletion 3p syndrome.
- Author
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Cargile CB, Goh DL, Goodman BK, Chen XN, Korenberg JR, Semenza GL, and Thomas GH
- Subjects
- Humans, In Situ Hybridization, Fluorescence, Infant, Karyotyping, Male, Microsatellite Repeats, Syndrome, Chromosome Deletion, Chromosomes, Human, Pair 3 genetics, Cytogenetic Analysis methods
- Abstract
Deletion 3p syndrome is associated with characteristic facial features, growth failure, and mental retardation. Typically, individuals with deletion 3p syndrome have terminal deletions that result in loss of material from 3p25 to 3pter. We present a child with a clinical phenotype consistent with deletion 3p syndrome (ptosis, microcephaly, growth retardation, and developmental delay) and a subtle interstitial deletion in the distal portion of the short arm of chromosome 3, del(3)(p25.3p26.2). Fluorescence in situ hybridization (FISH) studies using 3p subtelomeric probes confirmed the terminal region of chromosome 3 was present. Sequence tagged sites (STS)-linked BAC clones mapping to chromosomal region 3p25-p26 were used to characterize the interstitial deletion by FISH. The results indicate the deletion is within a region of approximately 4.5 Mb between STS markers D3S3630 and D3S1304. This interstitial deletion lies within all previously reported terminal deletions in deletion 3p syndrome individuals, and represents the smallest reported deletion associated with deletion 3p syndrome. Characterization of the deletion may help identify genes important to growth and development that contribute to the deletion 3p syndrome phenotype when present in a hemizygous state., (Copyright 2002 Wiley-Liss, Inc.)
- Published
- 2002
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28. Partial trisomy 7p defined by analysis of a complex chromosome rearrangement using a BAC clone panel.
- Author
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Tuck-Muller CM, Goodman BK, Li S, Martinez JE, Chen XN, Wertelecki W, Korenberg JR, and Stetten G
- Subjects
- Adolescent, Chromosomes ultrastructure, Chromosomes, Artificial, Bacterial, Cloning, Molecular, Ear pathology, Facies, Female, Foot pathology, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Chromosome Aberrations, Chromosome Disorders, Chromosomes, Human, Pair 7, Intellectual Disability genetics, Trisomy
- Abstract
Purpose: To illustrate the use of bacterial artificial chromosome (BAC) clone panels for molecular cytogenetic analysis of complex chromosome rearrangements (CCRs)., Methods: High resolution cytogenetics followed by fluorescence in situ hybridization (FISH) analysis using chromosome band-specific BAC probes, in addition to commercially available probes., Results: High resolution cytogenetics in conjunction with FISH using commercially available probes proved inadequate to resolve problems in characterizing a balanced CCR in the mother of a patient who had inherited an unbalanced form of the CCR. Accurate interpretation of the CCR and the unbalanced rearrangement in the patient as trisomy 7p12.2-->p21.3 was accomplished only through use of the BAC clone panel., Conclusion: Use of BAC clone panels can enhance the power of FISH analysis in defining chromosome rearrangements that cannot be resolved by high resolution chromosome analysis.
- Published
- 2001
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29. Hyperprolinaemia in patients with deletion (22)(q11.2) syndrome.
- Author
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Goodman BK, Rutberg J, Lin WW, Pulver AE, and Thomas GH
- Subjects
- Adolescent, Adult, Amino Acid Metabolism, Inborn Errors blood, Amino Acid Metabolism, Inborn Errors genetics, Biomarkers, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Syndrome, Amino Acid Metabolism, Inborn Errors enzymology, Chromosome Deletion, Chromosomes, Human, Pair 22, Proline blood, Proline Oxidase genetics
- Published
- 2000
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30. Delayed membranous ossification of the cranium associated with familial translocation (2;3)(p15;q12).
- Author
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Cargile CB, McIntosh I, Clough MV, Rutberg J, Yaghmai R, Goodman BK, Chen XN, Korenberg JR, Thomas GH, and Geraghty MT
- Subjects
- Adult, Female, Humans, In Situ Hybridization, Fluorescence, Infant, Newborn, Male, Pedigree, Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 3, Osteogenesis genetics, Skull growth & development, Translocation, Genetic
- Abstract
The relationship of delayed membranous cranial ossification to cranium bifidum and parietal foramina syndromes is unclear. We report on a family with delayed cranial membranous ossification (OMIM 155980) that segregates with an apparently balanced reciprocal translocation between chromosomes 2 and 3. The propositus had apparently low-set ears, proptosis, and a soft skull at birth. A radiographic survey of the skeleton showed markedly decreased ossification of the cranial bones and no other skeletal abnormalities. The mother and maternal grandmother of the propositus have brachycephaly, hypertelorism, and a history of a soft skull at birth. Chromosome analysis of peripheral blood from the propositus showed 46,XY,t(2;3)(p15;q12). The propositus, mother, and grandmother carry the same reciprocal translocation, whereas the mother's two phenotypically normal sibs have a normal karyotype. We used an STS-linked BAC resource to define the translocation breakpoint by identifying flanking BAC clones from both chromosomes 2, 1006D24 (D2S2279) and 1060A5 (D2S2231), and chromosome 3, 3D17 (WI8558) and 3D18 [CITB Human BAC Library, J.R.K.]. This represents the second report of a family with delayed membranous ossification of the cranium and the first report of the phenotype segregating with a chromosome rearrangement., (Copyright 2000 Wiley-Liss, Inc.)
- Published
- 2000
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31. Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia.
- Author
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Sacksteder KA, Biery BJ, Morrell JC, Goodman BK, Geisbrecht BV, Cox RP, Gould SJ, and Geraghty MT
- Subjects
- Amino Acid Sequence, Base Sequence, Chromosomes, Human, Pair 7 genetics, Cloning, Molecular, Consanguinity, DNA Mutational Analysis, Exons genetics, Female, Gene Expression Profiling, Genes, Recessive genetics, Homozygote, Humans, In Situ Hybridization, Fluorescence, Lysine metabolism, Male, Molecular Sequence Data, Multienzyme Complexes chemistry, Multienzyme Complexes metabolism, Physical Chromosome Mapping, RNA Splice Sites genetics, RNA, Messenger analysis, RNA, Messenger genetics, Saccharopine Dehydrogenases chemistry, Saccharopine Dehydrogenases metabolism, Sequence Alignment, Sequence Deletion genetics, Hyperlysinemias enzymology, Hyperlysinemias genetics, Multienzyme Complexes genetics, Mutation genetics, Saccharopine Dehydrogenases genetics
- Abstract
The first two steps in the mammalian lysine-degradation pathway are catalyzed by lysine-ketoglutarate reductase and saccharopine dehydrogenase, respectively, resulting in the conversion of lysine to alpha-aminoadipic semialdehyde. Defects in one or both of these activities result in familial hyperlysinemia, an autosomal recessive condition characterized by hyperlysinemia, lysinuria, and variable saccharopinuria. In yeast, lysine-ketoglutarate reductase and saccharopine dehydrogenase are encoded by the LYS1 and LYS9 genes, respectively, and we searched the available sequence databases for their human homologues. We identified a single cDNA that encoded an apparently bifunctional protein, with the N-terminal half similar to that of yeast LYS1 and with the C-terminal half similar to that of yeast LYS9. This bifunctional protein has previously been referred to as "alpha-aminoadipic semialdehyde synthase," and we have tentatively designated this gene "AASS." The AASS cDNA contains an open reading frame of 2,781 bp predicted to encode a 927-amino-acid-long protein. The gene has been sequenced and contains 24 exons scattered over 68 kb and maps to chromosome 7q31.3. Northern blot analysis revealed the presence of several transcripts in all tissues examined, with the highest expression occurring in the liver. We sequenced the genomic DNA from a single patient with hyperlysinemia (JJa). The patient is the product of a consanguineous mating and is homozygous for an out-of-frame 9-bp deletion in exon 15, which results in a premature stop codon at position 534 of the protein. On the basis of these and other results, we propose that AASS catalyzes the first two steps of the major lysine-degradation pathway in human cells and that inactivating mutations in the AASS gene are a cause of hyperlysinemia.
- Published
- 2000
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32. Quantitative neurologic assessment of ataxia-telangiectasia.
- Author
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Crawford TO, Mandir AS, Lefton-Greif MA, Goodman SN, Goodman BK, Sengul H, and Lederman HM
- Subjects
- Adolescent, Adult, Age Factors, Child, Child, Preschool, Cohort Studies, Data Interpretation, Statistical, Disease Progression, Humans, Infant, Linear Models, Observer Variation, Phenotype, Predictive Value of Tests, Prospective Studies, Reproducibility of Results, Ataxia Telangiectasia diagnosis, Neuropsychological Tests, Severity of Illness Index
- Abstract
Background: Ataxia telangiectasia (A-T) is a rare disorder with many distinctive neurologic features. Although there is substantial individual variation in the rate of progression of these features, their relationship to one another or to age has not been characterized., Methods: We formulated and tested multiple elements that assess different neurologic functions known to be affected by A-T. The overall index was applied to 52 patients with A-T, 2 to 29 years of age., Results: Seven elements items proved to be informative, and three elements were added based on face validity. In a linear regression model of individuals under 19 years of age, controlled for correlation within sibships, age accounted for 87% of the variation in the A-T Index., Conclusion: Despite substantial individual variability of the phenotypic elements of A-T, scores on this multidimensional index have a very high correlation with age, indicating that there is a characteristic rate of progression of the disease, although functional domains in the brain are differentially affected. The pattern of scores suggests that a severe and a mild form of A-T may be distinguished by this quantitative measure. With further development this index may become useful as an outcome measure for treatment studies and prognosis.
- Published
- 2000
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33. Molecular cytogenetic evaluation in a patient with a translocation (3;21) associated with blepharophimosis, ptosis, epicanthus inversus syndrome (BPES).
- Author
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Praphanphoj V, Goodman BK, Thomas GH, Niel KM, Toomes C, Dixon MJ, and Geraghty MT
- Subjects
- Adult, Cytogenetic Analysis, Eyelids abnormalities, Female, Follow-Up Studies, Humans, In Situ Hybridization, Fluorescence, Infant, Infant, Newborn, Infant, Premature, Karyotyping, Syndrome, Blepharophimosis genetics, Blepharoptosis genetics, Chromosomes, Human, Pair 21 genetics, Chromosomes, Human, Pair 3 genetics, Translocation, Genetic
- Abstract
Blepharophimosis, ptosis, epicanthus inversus syndrome type I (BPES; OMIM 110100) is an autosomal dominant disorder affecting craniofacial development and ovarian function. We have identified a patient with BPES who carried a de novo reciprocal translocation [46, XX,t(3;21)(q23;q22.1)]. Fluorescence in situ hybridization analysis at band 3q23 using probes derived from BAC 175G20 (Research Genetics), PACs 108L15 and 169C10 (RPCI1), and cosmids AC174D4, AC68D3, AC44F5, and AC125C5 (Lawrence Livermore National Laboratory) was performed. The patient's breakpoint was found to lie within the overlapping region of the BAC and PACs but centromeric to all the cosmids. However, a 10.5-kb BamHI-digested fragment, common to the BAC and PAC clones, was shown to cross the breakpoint. The results have placed our patient's breakpoint proximal to that of the previously reported patient [46,XY,t(3;4)(q23;p15.2)] and within a 10.5-kb interval. This is the second patient in which a breakpoint was refined by molecular cytogenetics. Our findings emphasize the significance of this region for BPES., (Copyright 2000 Academic Press.)
- Published
- 2000
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- View/download PDF
34. Cryptic subtelomeric translocations in the 22q13 deletion syndrome.
- Author
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Praphanphoj V, Goodman BK, Thomas GH, and Raymond GV
- Subjects
- Child, Preschool, Chromosome Mapping, Developmental Disabilities genetics, Female, Growth Disorders genetics, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Lymphocytes pathology, Microcephaly genetics, Muscle Hypotonia genetics, Abnormalities, Multiple genetics, Chromosome Deletion, Chromosomes, Human, Pair 22, Telomere genetics, Translocation, Genetic
- Abstract
Cryptic subtelomeric rearrangements are suspected to underlie a substantial portion of terminal chromosomal deletions. We have previously described two children, one with an unbalanced subtelomeric rearrangement resulting in deletion of 22q13-->qter and duplication of 1qter, and a second with an apparently simple 22q13-->qter deletion. We have examined two additional patients with deletions of 22q13-->qter. In one of the new patients presented here, clinical findings were suggestive of the 22q13 deletion syndrome and FISH for 22qter was requested. Chromosome studies suggested an abnormality involving the telomere of one 22q (46,XX,?add(22)(q13. 3)). FISH using Oncor D22S39 and Vysis ARSA probes confirmed a terminal deletion. A multi-telomere FISH assay showed a signal from 19qter on the deleted chromosome 22. Results were confirmed with 19qtel and 22qtel specific probes. The patient is therefore trisomic for 19qter and monosomic for 22qter. The patient's mother was found to have a translocation (19;22)(q13.42;q13.31). We also re-examined chromosomes from two patients previously diagnosed with 22q deletions who were not known to have a rearrangement using the multi-telomere assay. One of these patients was found to have a derivative chromosome 22 (der(22)t(6;22)(p25;q13)). No evidence of rearrangement was detected in the other patient. Thus we have found the 22q13 deletion to be associated with a translocation in three of four patients. This report illustrates the usefulness of examining patients with hypotonia, severe language delay, and mild facial dysmorphism for this syndrome and suggests that most of these deletions may be unbalanced subtelomeric rearrangements.
- Published
- 2000
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35. Clinical, cytogenetic, and fluorescence in situ hybridization findings in two cases of "complete ring" syndrome.
- Author
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Sigurdardottir S, Goodman BK, Rutberg J, Thomas GH, Jabs EW, and Geraghty MT
- Subjects
- Female, Humans, In Situ Hybridization, Fluorescence, Infant, Karyotyping, Male, Phenotype, Chromosomes, Human, Pair 4, Chromosomes, Human, Pair 9, Developmental Disabilities genetics, Growth Disorders genetics, Pigmentation Disorders genetics, Ring Chromosomes
- Abstract
The term "ring syndrome" was proposed to describe a phenotype of growth failure without major malformations due to a ring autosome. The growth failure is thought to be caused by instability of the ring chromosome leading to aneusomy and cell death. Most previous studies of ring chromosomes were based on standard cytogenetic banding techniques and were limited to microscopically detectable deletions in the ring chromosomes. We report on two patients with complete ring (4) and ring (9) chromosomes, respectively. The first was a 15-month-old girl and the second was a 16-month-old boy. They both presented with severe, symmetrical growth failure and normal psychomotor development in the absence of malformations. Their parents had a normal phenotype. The first case had a whorled pattern of hyperpigmentation and hypopigmentation on part of the face and chest, and the second case had a patchy hyperpigmented rash on the trunk. Peripheral blood karyotype of the first patient was 46,XX, r(4)(p16.3q35.2) and of the second 45,XY,-9/46,XY,r(9)(p24q34.3). G-band analysis suggested no loss of material in the ring chromosomes. These findings were confirmed by fluorescence in situ hybridization (FISH) analysis using chromosome-specific subtelomeric probes. The common human telomeric sequences were intact in the first patient but absent in the second patient. The cytogenetic and FISH data in our two cases provide further evidence for the existence of a "complete ring" phenotype independent of the autosome involved. Pigmentary skin changes are a useful clinical sign of mosaicism caused by the ring instability., (Copyright 1999 Wiley-Liss, Inc.)
- Published
- 1999
- Full Text
- View/download PDF
36. Molecular cytogenetic analysis and clinical findings in a newborn with prenatally diagnosed rec(7)dup(7q)inv(7)(p22q31.3)pat.
- Author
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Goodman BK, Stone K, Coddett JM, Cargile CB, Gurewitsch ED, Blakemore KJ, and Stetten G
- Subjects
- Abnormalities, Multiple diagnostic imaging, Abnormalities, Multiple genetics, Adult, Chromosome Aberrations diagnostic imaging, Chromosome Deletion, Chromosome Disorders, Chromosome Inversion, Diagnosis, Differential, Female, Fetal Diseases diagnostic imaging, Fetal Diseases genetics, Gene Duplication, Genetic Counseling, Humans, In Situ Hybridization, Fluorescence, Infant, Newborn, Male, Phenotype, Pregnancy, Chromosome Aberrations diagnosis, Chromosomes, Human, Pair 7, Fetal Diseases diagnosis, Ultrasonography, Prenatal
- Abstract
We report prenatal and early postnatal findings in a newborn with a partial trisomy of chromosome 7 (7q31.3-qter), arising from meiotic recombination of a paternal pericentric inversion, inv(7)(p22q31.3). The inversion breakpoints were localized and the regions of duplication and deletion were defined by fluorescence in situ hybridization (FISH) analysis using a series of locus-specific and subtelomeric probes. To our knowledge, only three cases involving a recombinant 7 with duplication of 7q have been reported, two of these being first cousins. The clinical findings in our patient included skeletal abnormalities, facial dysmorphism, dilated cerebral ventricles, microretrognathia and short neck. These findings and some aspects of the neonatal course were consistent with the phenotype previously reported for duplication of distal 7q, without associated monosomy for sequences from another chromosome., (Copyright 1999 John Wiley & Sons, Ltd.)
- Published
- 1999
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37. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter.
- Author
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Camacho JA, Obie C, Biery B, Goodman BK, Hu CA, Almashanu S, Steel G, Casey R, Lambert M, Mitchell GA, and Valle D
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Amino Acid Transport Systems, Basic, Animals, Canada, Carrier Proteins biosynthesis, Carrier Proteins chemistry, Chromosome Mapping, Female, France ethnology, Genetic Carrier Screening, Humans, Karyotyping, Male, Mice, Mitochondria metabolism, Mitochondrial Membrane Transport Proteins, Molecular Sequence Data, Neurospora crassa genetics, Ornithine metabolism, Point Mutation, Saccharomyces cerevisiae genetics, Sequence Alignment, Sequence Deletion, Sequence Homology, Amino Acid, Skin metabolism, Syndrome, Transfection, Amino Acid Metabolism, Inborn Errors genetics, Ammonia blood, Carrier Proteins genetics, Chromosomes, Human, Pair 13, Citrulline metabolism, Membrane Transport Proteins, Ornithine blood
- Abstract
Neurospora crassa ARG13 and Saccharomyces cerevisiae ARG11 encode mitochondrial carrier family (MCF) proteins that transport ornithine across the mitochondrial inner membrane. We used their sequences to identify EST candidates that partially encode orthologous mammalian transporters. We thereby identified such a gene (ORNT1) that maps to 13q14 and whose expression, similar to that of other urea cycle (UC) components, was high in liver and varied with changes in dietary protein. ORNT1 expression restores ornithine metabolism in fibroblasts from patients with hyperammonaemia-hyperornithinaemia-homocitrullinuria (HHH) syndrome. In a survey of 11 HHH probands, we identified 3 ORNT1 mutant alleles that account for 21 of 22 possible mutant ORNT1 genes in our patients: F188delta, which is common in French-Canadian HHH patients and encodes an unstable protein; E180K, which encodes a stable, properly targeted protein that is inactive; and a 13q14 microdeletion. Our results show that ORNT1 encodes the mitochondrial ornithine transporter involved in UC function and is defective in HHH syndrome.
- Published
- 1999
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38. Inherited duplication Xq27-qter at Xp22.3 in severely affected males: molecular cytogenetic evaluation and clinical description in three unrelated families.
- Author
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Goodman BK, Shaffer LG, Rutberg J, Leppert M, Harum K, Gagos S, Ray JH, Bialer MG, Zhou X, Pletcher BA, Shapira SK, and Geraghty MT
- Subjects
- Adult, Child, Child, Preschool, Family Health, Female, Growth Disorders genetics, Growth Disorders pathology, Humans, In Situ Hybridization, Fluorescence, Infant, Karyotyping, Male, Muscle Hypotonia genetics, Muscle Hypotonia pathology, Chromosome Aberrations, Chromosome Disorders, X Chromosome genetics
- Abstract
We describe the clinical phenotype in four males from three families with duplication (X)(qter-->q27::p22.3-->qter). This is an unusual duplication of the distal long arm segment, Xq27-qter, onto the distal short arm of the X chromosome at Xp22.3, as shown by fluorescent in situ hybridization analysis with multiple X-specific probes. The patients are young male offspring of three unrelated, phenotypically normal carrier women. The affected males have similar clinical manifestations including severe growth retardation and developmental delay, severe axial hypotonia, and minor anomalies. Such clinical similarity in three unrelated families demonstrates that this chromosome abnormality results in a new and distinct clinical phenotype. Replication studies, performed on two of the mothers, provided evidence that inactivation of the abnormal X chromosome permitted the structural abnormality to persist in these families for a generation or more in females without phenotypic expression.
- Published
- 1998
- Full Text
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39. DNA damage induced via independent generation of the radical resulting from formal hydrogen atom abstraction from the C1'-position of a nucleotide
- Author
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Tronche C, Goodman BK, and Greenberg MM
- Abstract
Background:. Deoxyribonucleotide radicals resulting from formal C1'-hydrogen atom abstraction are important reactive intermediates in a variety of DNA-damage processes. The reactivity of these radicals can be affected by the agents that generate them and the environment in which they are produced. As an initial step in determining the factors that control the reactivity of these important radical species, we developed a mild method for their generation at a defined site within a biopolymer. Results:. Irradiation of oligonucleotides containing a photolabile nucleotide produced C1'-DNA radicals. In the absence of potential reactants other than O2, approximately 90% of the damage events involve formation of alkaline-labile lesions, with the remainder resulting in direct strand breaks. The ratio of alkaline-labile lesions to direct strand breaks ( approximately 9:1) is independent of whether the radical is generated in single-stranded DNA or double-stranded DNA. Strand damage is almost completely quenched under anaerobic conditions in the presence of low thiol concentrations. Competition studies with O2 indicate that the trapping rate of C1'-DNA radicals by beta-mercaptoethanol is approximately 1.1 x 10(7) M-1 s-1. Conclusions:. The mild generation of the C1'-DNA radical in the absence of exogenous oxidants makes it possible to examine their intrinsic reactivity. In the absence of other reactants, the formation of direct strand breaks from C1'-radicals is, at most, a minor pathway. Competition studies between beta-mercaptoethanol and O2 indicate that significantly higher thiol concentrations than those in vivo or some means of increasing the effective thiol concentration near DNA are needed for these reagents to prevent the formation of DNA lesions arising from the C1'-radical under aerobic conditions.
- Published
- 1998
40. Familial tandem duplication of bands q31.1 to q32.3 on chromosome 4 with mild phenotypic effect.
- Author
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Goodman BK, Capone GT, Hennessey J, and Thomas GH
- Subjects
- Adult, Child, Child, Preschool, Chromosome Banding, Chromosome Disorders, Developmental Disabilities genetics, Female, Humans, Infant, Male, Pedigree, Phenotype, Trisomy genetics, Abnormalities, Multiple genetics, Chromosome Aberrations genetics, Chromosomes, Human, Pair 4 genetics
- Abstract
We describe a family carrying a direct duplication of an interstitial segment of the distal long arm of chromosome 4(q31.1q32.3) with a mild clinical phenotype. Affected family members include a 27-year-old woman and 2 of her 4 children, 1 of whom also has Klinefelter syndrome. Although 8 cases of simple duplications or insertions of 4q material have been described, only 3 include bands q31-q32, and these involve additional adjacent material. Affected members of the pedigree reported here have some of the manifestations of previously described cases of duplication 4q, but are less severely affected, suggesting that the genetic material in this region is well tolerated as a partial trisomy.
- Published
- 1997
- Full Text
- View/download PDF
41. Deletion of PTEN in a patient with Bannayan-Riley-Ruvalcaba syndrome suggests allelism with Cowden disease.
- Author
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Arch EM, Goodman BK, Van Wesep RA, Liaw D, Clarke K, Parsons R, McKusick VA, and Geraghty MT
- Subjects
- Adult, Alleles, Chromosome Mapping, Humans, Infant, Karyotyping, Male, PTEN Phosphohydrolase, Syndrome, Chromosomes, Human, Pair 10, Craniofacial Abnormalities genetics, Gene Deletion, Genes, Tumor Suppressor, Hamartoma Syndrome, Multiple genetics, Hemangioma genetics, Lipoma genetics, Phosphoric Monoester Hydrolases, Protein Tyrosine Phosphatases genetics, Tumor Suppressor Proteins
- Abstract
We report on an 18-month-old boy with an interstitial deletion at 10q23.2-q24.1. This region includes the PTEN gene, mutations of which have been reported to cause Cowden disease. Our patient presented with manifestations of Bannayan-Riley-Ruvalcaba (BRR) syndrome. The BRR syndrome is a rare disorder which presents most commonly in childhood. Cowden disease is a disease of adulthood and is inadequately described in children. Because of the considerable phenotypic overlap between the two disorders, and the cytogenetic and molecular findings in our patient, we suggest that BRR syndrome and Cowden disease are allelic.
- Published
- 1997
42. Delivery of cytosolic liver arginase into the mitochondrial matrix space: a possible novel site for gene replacement therapy.
- Author
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Wissmann PB, Goodman BK, Vockley JG, Kern RM, Cederbaum SD, and Grody WW
- Subjects
- Cell Line, Drug Delivery Systems, Humans, Mitochondria, Liver enzymology, Arginase genetics, Gene Transfer Techniques, Genetic Therapy, Mitochondria, Liver genetics
- Abstract
As a toxic metabolic byproduct in mammals, excess ammonia is converted into urea by a series of five enzymatic reactions in the liver that constitute the urea cycle. A portion of this cycle takes place in the mitochondria, while the remainder is cytosolic. Liver arginase (L-arginine ureahydrolase, A1) is the fifth enzyme of the cycle, catalyzing the hydrolysis of arginine to ornithine and urea within the cytosol. Patients deficient in this enzyme exhibit hyperargininemia with episodic hyperammonemia and long-term effects of mental retardation and spasticity. However, the hyperammonemic effects are not so catastrophic in arginase deficiency as compared to other urea cycle defects. Earlier studies have suggested that this is due to the mitigating effect of a second isozyme of arginase (AII) expressed predominantly in the kidney and localized within the mitochondria. In order to explore the curious dual evolution of these two isozymes, and the ways in which the intriguing, aspects of AII physiology might be exploited for gene replacement therapy of AI deficiency, the cloned cDNA for human AI was inserted into an expression vector downstream from the mitochondrial targeting leader sequence for the mitochondrial enzyme ornithine transcarbamylase and transfected into a variety of recipient cell types. AI expression in the target cells was confirmed by northern blot analysis, and competition and immunoprecipitation studies showed successful translocation of the exogenous AI enzyme into the transfected cell mitochondria. Stability studies demonstrated that the translocated enzyme had a longer half-life than either native cytosolic AI or mitochondrial AII. Incubation of the transfected cells with increasing amounts of arginine produced enhanced levels of mitochondrial AI activity, a substrate-induced effect that we have previously seen with native AII but never AI. Along with exploring the basic biological questions of regulation and subcellular localization in this unique dual-enzyme system, these results suggest that the mitochondrial matrix space may be a preferred site for delivery of enzymes in gene replacement therapy.
- Published
- 1996
- Full Text
- View/download PDF
43. Loss of function mutations in conserved regions of the human arginase I gene.
- Author
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Vockley JG, Goodman BK, Tabor DE, Kern RM, Jenkinson CP, Grody WW, and Cederbaum SD
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Conserved Sequence, Humans, Manganese metabolism, Molecular Sequence Data, Mutagenesis, Site-Directed, Neurospora, Pedigree, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, Rats, Sequence Alignment, Xenopus, Arginase genetics
- Abstract
We have utilized SSCP analysis to identify disease-causing mutations in a cohort with arginase deficiency. Each of the patient's mutations was reconstructed in vitro by site-directed mutagenesis to determine the effect of the mutations on enzyme activity. In addition we identified six areas of cross-species homology in the arginase protein, four containing conserved histidine residues thought to be important to Mn(2+)-dependent enzyme function. Mapping patient mutations in relationship to the conserved regions indicates that substitution mutations within the conserved regions and randomly occurring microdeletions and nonsense mutations have a significant effect on enzymatic function. In vitro mutagenesis was utilized to create nonpatient substitution mutations in the conserved histidine residues to verify their importance to arginase activity. As expected, replacement of histidine residues with other amino acids dramatically reduces arginase activity levels in our bacterial expression system.
- Published
- 1996
- Full Text
- View/download PDF
44. Functional and molecular analysis of liver arginase promoter sequences from man and Macaca fascicularis.
- Author
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Goodman BK, Klein D, Tabor DE, Vockley JG, Cederbaum SD, and Grody WW
- Subjects
- 3T3 Cells, Animals, Biological Evolution, Cell Line, DNA-Binding Proteins metabolism, Electrophoresis, Polyacrylamide Gel, Humans, Mice, Organ Specificity, Plasmids, Transcription, Genetic, Tumor Cells, Cultured, Arginase genetics, Liver enzymology, Macaca fascicularis genetics, Promoter Regions, Genetic
- Abstract
Functional and DNA binding analyses were used to investigate transcriptional regulation of liver arginase, a mammalian urea cycle enzyme with marked tissue specificity. Reporter constructs containing the proximal 111 bp of the gene from man and Macaca fascicularis showed over sixfold background activity in HepG2 hepatoma cells, which express significant levels of liver arginase, and 12-fold background activity in minimally expressing HEK cells. Longer constructs, active in both cell lines, showed greater activity in the liver cell line. The constructs showed no activity in arginase-negative NIH 3T3 fibroblasts. A 54-bp dyad insert present in the human sequence and absent in M. fascicularis did not affect function. DNA binding analyses localized multiple liver-specific complexes as well as complexes shared among cell types. Little binding was evident in fibroblast extracts. Despite liver-specific binding, there was no evidence of a strong liver-specific enhancer. HEK and NIH 3T3 nuclear extracts showed strikingly different patterns of DNA binding. These studies demonstrate that molecular regulation of liver arginase transcription is complex and that control mechanisms differ among tissue types.
- Published
- 1994
- Full Text
- View/download PDF
45. Identification of mutations (D128G, H141L) in the liver arginase gene of patients with hyperargininemia.
- Author
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Vockley JG, Tabor DE, Kern RM, Goodman BK, Wissmann PB, Kang DS, Grody WW, and Cederbaum SD
- Subjects
- Amino Acid Metabolism, Inborn Errors enzymology, Amino Acid Sequence, Conserved Sequence, Exons, Humans, Hyperargininemia, Molecular Sequence Data, Polymerase Chain Reaction, Sequence Analysis, DNA, Amino Acid Metabolism, Inborn Errors genetics, Arginase genetics, Arginine blood, Liver enzymology, Point Mutation
- Published
- 1994
- Full Text
- View/download PDF
46. Molecular genetic study of human arginase deficiency.
- Author
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Grody WW, Klein D, Dodson AE, Kern RM, Wissmann PB, Goodman BK, Bassand P, Marescau B, Kang SS, and Leonard JV
- Subjects
- Amino Acid Sequence, Amino Acids analysis, Arginase isolation & purification, Base Sequence, Blotting, Southern, Blotting, Western, Codon genetics, DNA isolation & purification, Heterozygote, Humans, Isoenzymes isolation & purification, Molecular Sequence Data, Oligodeoxyribonucleotides, Polymerase Chain Reaction methods, Reference Values, Restriction Mapping, Arginase genetics, DNA genetics, Hyperargininemia, Isoenzymes deficiency, Isoenzymes genetics, Liver enzymology, Skin enzymology
- Abstract
We have explored the molecular pathology in 28 individuals homozygous or heterozygous for liver arginase deficiency (hyperargininemia) by a combination of Southern analysis, western blotting, DNA sequencing, and PCR. This cohort represents the majority of arginase-deficient individuals worldwide. Only 2 of 15 homozygous patients on whom red blood cells were available had antigenically cross-reacting material as ascertained by western blot analysis using anti-liver arginase antibody. Southern blots of patient genomic DNAs, cut with a variety of restriction enzymes and probed with a near-full-length (1,450-bp) human liver arginase cDNA clone, detected no gross gene deletions. Loss of a TaqI cleavage site was identified in three individuals: in a homozygous state in a Saudi Arabian patient at one site, at a different site in homozygosity in a German patient, and in heterozygosity in a patient from Australia. The changes in the latter two were localized to exon 8, through amplification of this region by PCR and electrophoretic analysis of the amplified fragment after treatment with TaqI; the precise base changes (Arg291X and Thr290Ser) were confirmed by sequencing. It is interesting that the latter nucleotide variant (Thr290Ser) was found to lie adjacent to the TaqI site rather than within it, though whether such a conservative amino acid substitution represents a true pathologic mutation remains to be determined. We conclude that arginase deficiency, though rare, is a heterogeneous disorder at the genotypic level, generally encompassing a variety of point mutations rather than substantial structural gene deletions.
- Published
- 1992
47. Cytogenetic characterization of renal cell carcinoma in von Hippel-Lindau syndrome.
- Author
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Goodman MD, Goodman BK, Lubin MB, Braunstein G, Rotter JI, and Schreck RR
- Subjects
- Adult, Carcinoma, Renal Cell pathology, DNA, Neoplasm analysis, Humans, Kidney Neoplasms pathology, Male, Angiomatosis genetics, Carcinoma, Renal Cell genetics, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 8, Kidney Neoplasms genetics, Translocation, Genetic, von Hippel-Lindau Disease genetics
- Abstract
We report the case of a 26-year-old man with von Hippel-Lindau syndrome (VHL) and two renal cell carcinomas (RCC), one of which was studied cytogenetically. Chromosomal analysis of the RCC showed a translocation that involved chromosomes 3 and 8 with subsequent loss of the derivative chromosome 8. The patient's peripheral lymphocytes showed a normal karyotype that indicated that there was not a constitutional chromosomal translocation. This is the third reported case of RCC in a patient with VHL in which loss of a portion of the short arm of chromosome 3 (3p) has occurred. Similar chromosomal changes that involve 3p have been reported in both familial and sporadic cases of RCC and have led to speculation that a tumor suppressor gene may be located in this region. Cytogenetic characterization of renal tumors could assume increasing significance in the diagnosis and classification of RCC and potentially may guide therapy. These studies may also lead to a better understanding of the biologic behavior of RCC and result in more informed patient evaluation and counseling.
- Published
- 1990
- Full Text
- View/download PDF
48. Renting? Count your blessings.
- Author
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Goodman BK
- Subjects
- Dental Offices, Dentistry, Economics, Dental
- Published
- 1971
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