Charles Ma - Academia.edu (original) (raw)

Papers by Charles Ma

Nature Methods, 2010

We describe a method for conditional regulation of gene expression based on the processing of an ... more We describe a method for conditional regulation of gene expression based on the processing of an intron cassette by a splicing factor. The RNA processing factor MEC-8 is necessary for the function of the Caenorhabditis elegans touch receptor neurons; mec-8 mutants are touch insensitive. We show here that this insensitivity involves the loss of MEC-8-dependent splicing of mec-2, which encodes a component of the mechanosensory transduction complex. MEC-8 is needed to remove the ninth intron in mec-2 pre-mRNA to form the longest of three mRNAs, mec-2a. Without MEC-8, splicing causes the termination of the transcript. Inclusion of mec-2 intron 9 is sufficient to convey mec-8-dependent regulation on other genes and, in mec-8(u218ts) mutants, resulted in their temperature-dependent expression. Because mec-8 is expressed ubiquitously in embryos and extensively in larvae, this system should produce temperaturesensitive expression for most genes. We report a strain that exhibits temperature-dependent RNA interference.

Blood, 2011

1773 Risk stratification in chronic lymphocytic leukemia (CLL) is highly desirable and should com... more 1773 Risk stratification in chronic lymphocytic leukemia (CLL) is highly desirable and should comprise not only evaluation of clinical features but also molecular prognostic markers. Currently such molecular markers include loss of 17p13, 11q22, 13q14, 6q22, and gain of chromosome 12 as assessed by fluorescence in situ hybridization (FISH) and mutation status of the variable region of the IGH gene (IGHV) by sequencing. In recent years, genome-wide scanning technologies such as array-comparative genomic hybridization (array-CGH) have revealed novel and refined known copy number alterations (CNAs) in the CLL genome. In order to evaluate the potential of array-CGH in prognostication in mature B-cell neoplasms, including CLL, and implement array-CGH in a clinical diagnostic laboratory, a targeted oligonucleotide-based microarray was custom designed to represent genomic regions exhibiting gain/loss in these lymphoid neoplasms. The 4 × 44K formatted array included 2 × 17,348 probes for th...

Journal of Clinical Oncology, 2015

428 Background: About one-third of patients with clear cell renal cell carcinoma (ccRCC) exhibit ... more 428 Background: About one-third of patients with clear cell renal cell carcinoma (ccRCC) exhibit metastasis at the time of diagnosis and show poor prognosis. The genetic and epigenetic alterations associated with metastasis in ccRCC have variably been studied, and their role in the metastatic process is unclear. The goals of the current study were to identify genomic copy number alterations (CNAs) associated with ccRCC metastasis and examine their clinical utility. Methods: In this IRB-approved study, genome-wide copy number profiling was performed on DNA from 144 ccRCC (81 primary and 63 metastatic lesions). Differential CNAs between primary and metastatic lesions and between different metastatic sites were identified using Fisher’s exact test. Associations between CNAs and overall survival (OS) were tested using the log rank statistic and Kaplan-Meier method. Genomic profiling data of 437 and 240 primary ccRCC (TCGA and PMID: 23797736, respecitively) were used for verification. Re...

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, Jun 11, 2016

A predominantly diffuse growth pattern and CD23 co-expression are uncommon findings in nodal foll... more A predominantly diffuse growth pattern and CD23 co-expression are uncommon findings in nodal follicular lymphoma and can create diagnostic challenges. A single case series in 2009 (Katzenberger et al) proposed a unique morphologic variant of nodal follicular lymphoma, characterized by a predominantly diffuse architecture, lack of the t(14;18) IGH/BCL2 translocation, presence of 1p36 deletion, frequent inguinal lymph node involvement, CD23 co-expression, and low clinical stage. Other studies on CD23+ follicular lymphoma, while associating inguinal location, have not specifically described this architecture. In addition, no follow-up studies have correlated the histopathologic and cytogenetic/molecular features of these cases, and they remain a diagnostic problem. We identified 11 cases of diffuse, CD23+ follicular lymphoma with histopathologic features similar to those described by Katzenberger et al. Along with pertinent clinical information, we detail their histopathology, IGH/BCL2...

Leukemia & lymphoma, Jan 21, 2015

Genomic copy number alterations (CNAs) in diffuse large B-cell lymphoma (DLBCL) have roles in dis... more Genomic copy number alterations (CNAs) in diffuse large B-cell lymphoma (DLBCL) have roles in disease pathogenesis but overall clinical relevance remains unclear. Herein, an unbiased algorithm was uniformly applied across three genome profiling datasets comprising 392 newly-diagnosed DLBCL specimens that defined 32 overlapping CNAs, involving 36 minimal common regions (MCRs). Scoring criteria were established for 50 aberrations within the MCRs while considering peak gains/losses. Application of these criteria to independent datasets revealed novel candidate genes with coordinated expression, such as CNOT2, potentially with pathogenic roles. No one single aberration significantly associated with patient outcome across datasets, but genomic complexity, defined by imbalance in more than one MCR, significantly portended adverse outcome in two of three independent datasets. Thus, the standardized scoring of CNAs currently developed can be uniformly applied across platforms, affording rob...

Blood, 2015

Background: Recent advancements in comprehensive sequencing technologies has enabled researchers ... more Background: Recent advancements in comprehensive sequencing technologies has enabled researchers to uncover numerous somatic variants within many disease types, but their respective contributions to disease pathogenesis and potential roles as outcome biomarkers are less well-defined. Even fewer studies have integrated somatic mutation events with genomic gain and loss events of respective genes, mostly due to the need to utilize a second platform to robustly assess genomic copy number. To further understand the roles of these genomic aberrations in the disease biology of mature B-cell neoplasms, we developed a next-generation sequencing (NGS) panel of 220 genes for profiling of Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), and secondarily for Chronic Lymphocytic Leukemia (CLL). Methods: The 220 genes represented in the panel included genes based on reported frequency of mutations, targets of therapeutic agents, involvement in disease-en...

Journal of Urology, 2015

Purpose: Accurate discrimination of benign oncocytoma and malignant renal cell carcinoma is usefu... more Purpose: Accurate discrimination of benign oncocytoma and malignant renal cell carcinoma is useful for planning appropriate treatment strategies for patients with renal masses. Classification of renal neoplasms solely based on histopathology can be challenging, especially the distinction between chromophobe renal cell carcinoma and oncocytoma. In this study we develop and validate an algorithm based on genomic alterations for the classification of common renal neoplasms. Materials and Methods: Using TCGA renal cell carcinoma copy number profiles and the published literature, a classification algorithm was developed and scoring criteria were established for the presence of each genomic marker. As validation, 191 surgically resected formalin fixed paraffin embedded renal neoplasms were blindly submitted to targeted array comparative genomic hybridization and classified according to the algorithm. CCND1 rearrangement was assessed by fluorescence in situ hybridization. Results: The optimal classification algorithm comprised 15 genomic markers, and involved loss of VHL, 3p21 and 8p, and chromosomes 1, 2, 6, 10 and 17, and gain of 5qter, 16p, 17q and 20q, and chromosomes 3, 7 and 12. On histological rereview (leading to the exclusion of 3 specimens) and using histology as the gold standard, 58 of 62 (93%) clear cell, 51 of 56 (91%) papillary and 33 of 34 (97%) chromophobe renal cell carcinomas were classified correctly. Of the 36 oncocytoma specimens 33 were classified as oncocytoma (17 by array comparative genomic hybridization and 10 by array comparative genomic hybridization plus fluorescence in situ hybridization) or benign (6). Overall 93% diagnostic sensitivity and 97% specificity were achieved.

Cancer Genetics, 2012

Cancer Cytogenomics Microarray Consortium Third Annual Meeting, August 6e7, 2012 SESSION1:HEMATOL... more Cancer Cytogenomics Microarray Consortium Third Annual Meeting, August 6e7, 2012 SESSION1:HEMATOLOGICMALIGNANCIES Clinical Laboratory Implementation of the Detection of Genomic Aberrations in Formalin-Fixed ParaffinEmbedded Small Lymphocytic Lymphoma Specimens by Array-CGH Charles Ma, Asha N. Guttapalli, Lizalynn M. Dias, Lynnette M. Cahill, Lan Wang, Jane Houldsworth Cancer Genetics Inc., Rutherford, NJ Due to the highly variable course of the disease, risk stratification is essential for the management of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients. For CLL, assessment of prognostic molecular markers including IGHV mutation status and specific genomic aberrations by either FISH and/or, more recently, array-CGH is routinely performed. The same molecular markers have been shown to offer similar prognostic value in SLL. However, the clinical diagnostic evaluation of these markers in SLL is hampered by the solid tissue type. Indeed, formalin-fixed, paraffin-embedded (FFPE) material is often the only available specimen for analysis. Using over 300 FFPE samples, we have established appropriate laboratory procedures and QC matrices for the clinical implementation of array-CGH for FFPE samples. In brief, DNA is extracted from 5 ten micron FFPE sections, and then a minimum of 1ug of DNA is heat fragmented, labeled enzymatically, and hybridized with a similarly fragmented commercial reference DNA to a custom-designed DNA oligonucleotide microarray representing genomic regions that are commonly altered in mature B-cell neoplasms. For ten SLL FFPE samples, adequate DNA was isolated and found to be of varied quality. Using ADM-2, the same genomic aberrations as commonly found in CLL (13q14 loss (MIR15A/16-1), 17p13 loss (TP53), and 11q22 loss (ATM)) were detected in the SLL specimens with high reproducibility and accuracy. DNA dilution studies indicated an analytical sensitivity of 60%70% while FISH in the specimens for detected aberrations revealed sensitivity closer to 30%-40%. All aberrations detected by array-CGH were independently validated by quantitative PCR for genes mapped within the respective regions. Thus, our data indicated that array-CGH is suitable for the detection 2210-7762/$ see front matter a 2012 Elsevier Inc. Elsevier Inc. http://dx.doi.org/10.1016/j.cancergen.2012.07.004 of prognostic genomic aberrations in SLL in a clinical diagnostic setting that could be implemented in patient risk stratification. Conflict of Interest: These authors are employees of Cancer Genetics, Inc., Rutherford, NJ. Array-Based Karyotyping Post Plasma Cell Enrichment for the Detection of Genomic Abnormalities in Multiple Myeloma Barbara K. Zehentner , Luise Hartmann , Krystal Johnson , Christine Stephenson , Douglas Chapman , Monica de Baca , Denise A. Wells , Michael R. Loken , Budi Tirtorahardjo , Shelly R. Gunn , Lony Lim b HematoLogics Inc., Seattle WA; Combimatrix, Irvine, CA Multiple myeloma (MM) is a hematopoietic neoplasm characterized by malignant plasma cells. The discovery of genomic abnormalities present in the monoclonal plasma cells has diagnostic, prognostic, as well as disease monitoring implications. However, technical and disease-related limitations hamper the detection of these abnormalities by metaphase cytogenetic analysis or FISH. In this study, we tested 28 bone marrow specimens with known plasma cell neoplasm for the presence of genomic abnormalities using microarray analysis post plasma cell enrichment and compared the results with other laboratory findings. Metaphase cytogenetic studies were performed on 15 of the 28 samples and identified disease-related genomic aberrations in only 3 of the 15 cases (20%) due to the low proliferative rate of plasma cells; 84.6% of specimens tested positive by MACS-FISH and 89.3% by array comparative genomic hybridization (aCGH). Furthermore, aCGH detected additional abnormalities in 24 cases as compared with FISH alone. We conclude that the combination of plasma cell enrichment and genomic copy number assessment using CGH microarray is a valuable approach for routine clinical use to achieve a more complete genetic characterization of multiple myeloma patients. Conflict of Interest: Employment, stock ownership.

Cell, 2004

that production of fluorescence from partial GFP polypeptides, which we refer to as reconstituted... more that production of fluorescence from partial GFP polypeptides, which we refer to as reconstituted GFP (recGFP), can be used to monitor protein-protein interactions. Hu et al. (2002) have subsequently used this property to demonstrate interactions among bZIP and