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Michael Baudis

Publications and source records attributed to Michael Baudis.

8 recordsLinked to original sources
PubMed2006

Distance-based clustering of CGH data.

MOTIVATION: We consider the problem of clustering a population of Comparative Genomic Hybridization (CGH) data samples. The goal is to develop a systematic way of placing patients with similar CGH imbalance profiles into the same cluster. Our expectation is that patients with the same cancer types will generally belong to the same cluster as their underlying CGH profiles will be similar. RESULTS: We focus on distance-based clustering strategies. We do this in two steps. (1) Distances of all pairs of CGH samples are computed. (2) CGH samples are clustered based on this distance. We develop three pairwise distance/similarity measures, namely raw, cosine and sim. Raw measure disregards correlation between contiguous genomic intervals. It compares the aberrations in each genomic interval separately. The remaining measures assume that consecutive genomic intervals may be correlated. Cosine maps pairs of CGH samples into vectors in a high-dimensional space and measures the angle between them. Sim measures the number of independent common aberrations. We test our distance/similarity measures on three well known clustering algorithms, bottom-up, top-down and k-means with and without centroid shrinking. Our results show that sim consistently performs better than the remaining measures. This indicates that the correlation of neighboring genomic intervals should be considered in the structural analysis of CGH datasets. The combination of sim with top-down clustering emerged as the best approach. AVAILABILITY: All software developed in this article and all the datasets are available from the authors upon request. CONTACT: juliu@cise.ufl.edu.

Algorithms↗
PubMed2006

ABCB1 over-expression and drug-efflux in acute lymphoblastic leukemia cell lines with t(17;19) and E2A-HLF expression.

BACKGROUND: The t(17;19)(q21;p13), which occurs in a small subset of acute lymphoblastic leukemias (ALLs) and is associated with a dismal prognosis, creates a chimeric E2A-HLF transcription factor with transforming properties. PROCEDURE: We used representational difference analysis to identify candidate E2A-HLF target genes. Transient transfection assays and an inducible expression model system were then used to evaluate the ability of E2A-HLF to modulate target gene expression. RESULTS: We identified ABCB1 (MDR1, P-glycoprotein) as a gene differentially expressed in ALL cell lines with and without E2A-HLF expression and demonstrated that t(17;19)+ ALL cell lines expressed high levels of ABCB1 protein and had a drug efflux-positive phenotype. Although ABCB1 transcription is regulated by C/EBPbeta via interaction with a DNA response element that shares significant homology with the optimal E2A-HLF binding site, E2A-HLF did not directly activate transcription of reporter genes under control of ABCB1 promoter elements in transient transfection assays. However, ABCB1 expression was induced in a DNA-binding independent manner by E2A-HLF, E2A-PBX1, and truncated E2A polypeptides consisting of those portions of E2A present in leukemic fusion proteins. CONCLUSIONS: E2A-HLF-mediated over-expression of ABCB1 may play a critical role in defining the clinical phenotype of ALLs with a t(17;19), suggesting pharmacologic modulation of ABCB1 activity as a rational therapeutic strategy for this chemotherapy resistant subtype of ALL.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Allele-specific loss of heterozygosity in multiple colorectal adenomas: toward an integrated molecular cytogenetic map II.

Colorectal cancer (CRC) remains a significant public health challenge despite our increased understanding of the genetic defects underlying the pathogenesis of this common disease. It has been thought that multiple mechanisms lead to the malignant phenotype, with familial predisposition syndromes accounting for only a small proportion of all CRC cases. To identify additional loci likely involved in CRC and to test the hypothesis of allele-specific loss of heterozygosity (LOH) for the localization of CRC susceptibility genes, we initially conducted a genome-wide allelotyping analysis of 48 adenomas from a patient with familial adenomatous polyposis coli (FAP) and 63 adenomas from 7 patients with sporadic CRC using 79 fluorescently tagged oligonucleotide primers amplifying microsatellite loci covering the human genome. Frequent allelic losses were identified at D17S802 (41%), D7S518 (40%), D18S53 (38%), D10S249 (32%), D2S391 (29%), D16S419 (27%), D15S1005 and D15S120 (24%), D9S274 and D11S1318 (23%), D14S65 (20%), D14S274 and D17S953 (19%), D19S424 (18%), D5S346 and D1S397 (15%), and D6S468 (13%) in multiple FAP adenomas. Common LOH was also detected at D4S1584 (42%), D11S968 (31%), D17S953 (28%), D5S394, D9S286 and D10S249 (24%), D8S511 (23%), D13S158 (21%), D7S669 (20%), D18S58 (19%), D2S162 and D16S432 (16%), D2S206 (15%), D7S496 and D17S946 (14%), D6S292 (13%), D4S1586 and D8S283 (11%), and D1S2766 (10%) in multiple CRC adenomas. In addition, allele-specific LOH at D5S346, D15S1005, and D15S120 was observed in multiple FAP adenomas (P < 0.01) and at D2S206 and D16S423 in multiple CRC (P < 0.05). To compare our data to previous reports, we determined the band-specific frequency of chromosomal imbalances in CRC karyotypes reported in the Mitelman database, and from the CGH results of cases accessible through the PROGENETIX website. Furthermore, published genome-wide allelotyping analysis of CRC and other allele-specific LOH studies were compiled and collated with our LOH data. The combined results not only provide a comprehensive view of genetic losses in CRC, indicating the comparability of these different techniques, but they also reveal different novel loci in multiple adenomas from FAP and sporadic CRC patients, suggesting that they represent a distinct subtype of CRC in terms of allelic losses. Allele-specific LOH is an alternative approach for cancer gene mapping.

Aged↗
PubMed2005

Genetic losses in breast cancer: toward an integrated molecular cytogenetic map.

Breast cancer is the most common malignant disease in Caucasian women, but is less frequent in Chinese women. The molecular basis for such ethnical difference in disease pathogenesis remains unknown. To address this issue, we performed allelotyping analysis of formalin-fixed, paraffin-embedded samples from 21 Chinese patients with breast cancer using 59 fluorescently tagged oligonucleotide primers amplifying microsatellite loci. Loss of heterozygosity (LOH) was found in all tumor samples. Frequent allelic losses were identified at markers D3S1578 (56%); D7S507 (55%); D1S2766 (50%); D17S789 and D17S946 (43% each); D19S814 (35%); D2S162, D13S158 and D13S296 (33% each); D1S551 and D1S2800 (29% each); D3S1597 and D6S260 (22% each); and D1S1588 (21%). To compare our data to previous reports, we determined the band-specific frequency of chromosomal imbalances in breast cancer karyotypes reported in the Mitelman database, and from the CGH results of cases accessible through the Progenetix website. Furthermore, published LOH analyses of breast cancer cases were compared to our own LOH results, demonstrating the most common chromosomal regions affected by allelic losses. The combined results provide a comprehensive view of genetic losses in breast cancers, indicating the comparability of these different techniques and suggesting the presence of a distinct subset of breast cancers with high-frequency LOH at chromosomes 1 and 2p in Chinese patients.

Alleles↗
PubMed2005

Microarray comparative genomic hybridization detection of chromosomal imbalances in uterine cervix carcinoma.

BACKGROUND: Chromosomal Comparative Genomic Hybridization (CGH) has been applied to all stages of cervical carcinoma progression, defining a specific pattern of chromosomal imbalances in this tumor. However, given its limited spatial resolution, chromosomal CGH has offered only general information regarding the possible genetic targets of DNA copy number changes. METHODS: In order to further define specific DNA copy number changes in cervical cancer, we analyzed 20 cervical samples (3 pre-malignant lesions, 10 invasive tumors, and 7 cell lines), using the GenoSensor microarray CGH system to define particular genetic targets that suffer copy number changes. RESULTS: The most common DNA gains detected by array CGH in the invasive samples were located at the RBP1-RBP2 (3q21-q22) genes, the sub-telomeric clone C84C11/T3 (5ptel), D5S23 (5p15.2) and the DAB2 gene (5p13) in 58.8% of the samples. The most common losses were found at the FHIT gene (3p14.2) in 47% of the samples, followed by deletions at D8S504 (8p23.3), CTDP1-SHGC- 145820 (18qtel), KIT (4q11-q12), D1S427-FAF1 (1p32.3), D9S325 (9qtel), EIF4E (eukaryotic translation initiation factor 4E, 4q24), RB1 (13q14), and DXS7132 (Xq12) present in 5/17 (29.4%) of the samples. CONCLUSION: Our results confirm the presence of a specific pattern of chromosomal imbalances in cervical carcinoma and define specific targets that are suffering DNA copy number changes in this neoplasm.

Cell Line, Tumor↗
PubMed2005

Unequivocal delineation of clinicogenetic subgroups and development of a new model for improved outcome prediction in neuroblastoma.

PURPOSE: Neuroblastoma is a genetically heterogeneous pediatric tumor with a remarkably variable clinical behavior ranging from widely disseminated disease to spontaneous regression. In this study, we aimed for comprehensive genetic subgroup discovery and assessment of independent prognostic markers based on genome-wide aberrations detected by comparative genomic hybridization (CGH). MATERIALS AND METHODS: Published CGH data from 231 primary untreated neuroblastomas were converted to a digitized format suitable for global data mining, subgroup discovery, and multivariate survival analyses. RESULTS: In contrast to previous reports, which included only a few genetic parameters, we present here for the first time a strategy that allows unbiased evaluation of all genetic imbalances detected by CGH. The presented approach firmly established the existence of three different clinicogenetic subgroups and indicated that chromosome 17 status and tumor stage were the only independent significant predictors for patient outcome. Important new findings were: (1) a normal chromosome 17 status as a delineator of a subgroup of presumed favorable-stage tumors with highly increased risk; (2) the recognition of a survivor signature conferring 100% 5-year survival for stage 1, 2, and 4S tumors presenting with whole chromosome 17 gain; and (3) the identification of 3p deletion as a hallmark of older age at diagnosis. CONCLUSION: We propose a new regression model for improved patient outcome prediction, incorporating tumor stage, chromosome 17, and amplification/deletion status. These findings may prove highly valuable with respect to more reliable risk assessment, evaluation of clinical results, and optimization of current treatment protocols.

Adolescent↗
PubMed2002

Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma.

PURPOSE: This trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group compares the use of high-dose therapy (HDT) as part of primary treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus etoposide followed by involved-field (IF) radiotherapy in a randomized, multicenter, phase III study. PATIENTS AND METHODS: Three hundred twelve patients with "aggressive" non-Hodgkin's lymphoma aged <or= 60 years with elevated serum lactate dehydrogenase levels were included from 1990 to 1997. Patients with at least a minor response after two cycles of CHOEP (CHOP + etoposide 3 x 100 mg/m(2)) were to receive three further cycles of CHOEP followed by IF radiotherapy (arm A) or one further cycle of CHOEP followed by autologous stem-cell transplantation and IF radiotherapy (arm B). RESULTS: Among 158 patients randomized to arm B, 103 (65%) received HDT. The complete remission rate at the end of treatment was 62.9% in arm A and 69.9% in arm B. With a median observation time of 45.5 months, overall survival for all 312 patients was 63% after 3 years (63% for arm A, 62% for arm B; P =.68). Event-free survival was 49% for arm A versus 59% for arm B (P =.22). Relapse in arm B was associated with a significantly worse survival rate than relapse in arm A (P <.05). Relapse after HDT occurred early (median interval, 3 months). Six patients developed secondary neoplasia, three in arm A and three in arm B. CONCLUSION: Results of the randomized trial comparing CHOP-like chemotherapy with early HDT do not support the use of HDT with carmustine, etoposide, cytarabine, and melphalan following shortened standard chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗