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C R Bartram

Publications and source records attributed to C R Bartram.

At least 19 recordsLinked to original sources
PubMed2006

Folate metabolic gene polymorphisms and childhood acute lymphoblastic leukemia: a case-control study.

We genotyped six folate metabolic pathway genes for 11 polymorphisms in 460 cases of childhood acute lymphoblastic leukemia (ALL) and 552 ethnically matched controls. None of the polymorphisms except the 66A>G (I22M) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene showed any effect on disease risk. The carriers of the G-allele were associated with a marginal decreased risk of ALL (gender-adjusted global P=0.03; multiple-testing corrected P=0.25). Analysis of four polymorphisms in the MTRR gene showed statistically significant differences in haplotype distribution between cases and controls (global P<0.0001). The haplotypes GCAC (odds ratio (OR) 0.5, 95% confidence interval (CI) 0.4-0.6) and ATAC (OR 0.5, 95% CI 0.3-0.6) were associated with a reduced risk and the haplotypes ACAC (OR 2.3, 95% CI 1.8-2.9) and GTAC (OR 1.8, 95% CI 1.4-2.3) with an increased risk. The genotype-combination analyses indicated that the best model stratifies cases and controls based on the 66A>G and the 524C>T polymorphisms in the MTRR gene (global P=0.03). Our results suggest that, besides a weak association of childhood ALL with the 66A>G polymorphism, haplotypes within the MTRR gene may, in part, account for population-based differences in risk.

Adolescent↗
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗
PubMed2004

High incidence and unique features of antigen receptor gene rearrangements in TEL-AML1-positive leukemias.

The t(12;21) translocation resulting in the TEL-AML1 gene fusion is found in 25% of childhood B-cell precursor (BCP) acute lymphoblastic leukemias (ALL). Since TEL-AML1 has been reported to induce cell cycle retardation and thus may influence somatic recombination, we analyzed 214 TEL-AML1-positive ALL by PCR for rearrangements of the immunoglobulin (Ig) and T-cell receptor (TCR) genes. As a control group, 174 childhood BCP ALL without a TEL-AML1 were used. The majority of TEL-AML1-positive leukemias had a higher number of Ig/TCR rearrangements than control ALL. They also had a more mature immunogenotype characterized by their high frequency of complete IGH, IGK-Kde, and TCRG rearrangements. While IGK-Kde and TCRG were more frequently rearranged on both alleles at higher age, IGH and TCRD rearrangements decreased in their incidence along with a decrease in biallelic IGH rearrangements. This suggests that the recombination process continues in these leukemias leading to ongoing rearrangements and possibly also deletions of antigen receptor genes. We here provide first evidence that somatic recombination of antigen receptor genes is affected by the TEL-AML1 fusion, and that further age-related differences are probably caused by the longer latency period of the prenatally initiated TEL-AML1-positive leukemias in older children.

Adolescent↗
PubMed2003

Long-term study of the clinical significance of loss of heterozygosity in childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is one of the most common malignancies in childhood, with a widely variable outcome. Differences in the behavior and prognosis of the leukemia suggest that ALL can be divided into several biologic subgroups. We analyzed the loss of heterozygosity (LOH) of 6q, 9p, 11q and 12p using 31 microsatellite sites to determine their overall frequency and clinical value. We have studied 244 primary ALL samples obtained from the Multicenter Trial ALL-BFM 90 of Childhood ALL group. These patients have now been followed clinically for over 8 years. LOH occurred in 169 (69%) individuals in the following frequencies: 6q, 49 patients (20%); 9p, 97 patients (40%); 11q, 29 patients (12%); 12p, 60 patients (25%). Clinical data showed that those with 6q LOH were younger (P = 0.01) and had lower WBC counts (P = 0.02); patients with 9p LOH more frequently had CNS involvement (P = 0.01) and T cell phenotype (P = 0.0001); individuals with 11q LOH had a good response to induction chemotherapy (P = 0.02); those with 12p LOH were younger (P = 0.005), frequently had precursor B ALL (P = 0.001), and had a longer event-free survival (P = 0.05). Taken together, these data confirm that LOH is a very frequent alteration in childhood ALL.

B-Lymphocytes↗
PubMed2002

Disruption of the RanBP17/Hox11L2 region by recombination with the TCRdelta locus in acute lymphoblastic leukemias with t(5;14)(q34;q11).

The t(5;14)(q33-34;q11) translocation constitutes a recurrent rearrangement in acute lymphoblastic leukemia involving the T cell receptor (TCR) delta locus on chromosome 14. Breakpoint sequences of the derivative chromosome 5 were isolated by application of a ligation-mediated PCR technique using TCR delta-specific primers to amplify genomic DNA from the leukemic cells of a patient with t(5;14). Through exon trap analysis, we identified various putative exons of the chromosome 5 target gene of the translocation; compilation of sequence information of trapped exons and available expressed sequence tags (ESTs) from the GenBank database allowed us to assemble 1.2 kb of the cDNA. Full-length cDNAs were isolated from a human testis cDNA library and sequence analysis predicted a putative Ran binding protein, a novel member of the importin-beta superfamily of nuclear transport receptors, called RanBP17. The t(5;14) breakpoint maps to the 3' coding region of the gene. The breakpoint of a second t(5;14) positive patient was mapped about 8 kb downstream of the most 3' RanBP17 exon and 2 kb upstream of the first exon of the orphan homeobox gene, Hox11L2. In both cases TCR delta enhancer sequences are juxtaposed downstream of the truncated or intact RanBP17 gene, respectively on the derivative chromosome.

Acute Disease↗
PubMed2001

Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course.

Sixty-four patients with adult T-cell leukemia/lymphoma (ATL; 18 patients with indolent subtype and 46 with aggressive subtype) associated with human T-lymphotropic virus type 1 (HTLV-1) were analyzed using comparative genomic hybridization (CGH). The most frequent observations were gains at chromosomes 14q, 7q, and 3p and losses at chromosomes 6q and 13q. Chromosome imbalances, losses, and gains were more frequently observed in aggressive ATL than in indolent ATL, with significant differences between the 2 ATL subtypes at gains of 1q and 4q. An increased number of chromosomal imbalances was associated with a significantly shorter survival in all patients. A high number of chromosomal losses was associated with a poor prognosis in indolent ATL, whereas the presence of 7q+ was marginally associated with a good prognosis in aggressive ATL. Paired samples (ie, samples obtained at different sites from 4 patients) and sequential samples from 13 patients (from 6 during both chronic disease and acute crisis and from 7 during both acute onset and relapse) were examined by CGH and Southern blotting for HTLV-1. All but 2 paired samples showed differences on CGH assessment. Two chronic/crisis samples showed distinct results regarding both CGH and HTLV-1 integration sites, indicating clonal changes in ATL at crisis. In 11 patients, the finding of identical HTLV-1 sites and clonally related CGH results suggested a common origin of sequential samples. In contrast to chronic/crisis samples, CGH results with all acute/relapse sample pairs showed the presence of clonally related but not evolutional subclones at relapse, thereby suggesting marked chromosomal instability. In summary, clonal diversity is common during progression of ATL, and CGH alterations are associated with clinical course. (Blood. 2001;97:3875-3881)

Adult↗
PubMed2001

Chromosomal aberrations in sporadic pituitary tumors.

Pituitary adenomas are common intracranial neoplasms that may be hormone-secreting or nonfunctional. Genetic defects associated with some pituitary tumors have been identified, although our understanding of the underlying molecular mechanisms remains incomplete. We have studied 75 sporadic pituitary tumors, representing the major clinical subtypes, by comparative genomic hybridization (CGH) with the aim of assessing for DNA copy number changes. CGH revealed chromosomal imbalances in 34 adenomas (45.3%), whereby gains were 4.9 times more frequently observed than losses. Most of the genetic alterations detected by CGH affected entire chromosomes (108/131, 82.4%). Gain of genetic material was observed predominantly on chromosomes X (24/75, 32%), 19 (12/75, 16%), 12 (6/75, 6.7%), 7 and 9 (5/75, 6.7%), whereas loss of DNA sequences most frequently affected chromosomes 11 (4/75, 5.3%), 13 and 10 (3/75, 4%). There were no significant differences in the CGH results for the individual clinical subtypes of pituitary tumors. These results reveal a nonrandom pattern of chromosomal alterations in pituitary tumors, in particular gains of entire chromosomes, and this may contribute to the development of such neoplasms.

Adenoma↗
PubMed2001

Comparative genomic hybridization in childhood acute lymphoblastic leukemia: correlation with interphase cytogenetics and loss of heterozygosity analysis.

We used comparative genomic hybridization (CGH) to study DNA copy number changes in 71 children with acute lymphoblastic leukemia (ALL) including 50 B-lineage and 21 T-ALLs. Forty-two patients (59%) showed genomic imbalances whereby gains were more frequently observed than losses (127 vs. 29). Gains most commonly affected the entire chromosomes 21 and 10 (19.7% each), 6, 14, 18, X (15.5% each), 17 (14.1%) and 4 (11.3%). Highly hyperdiploid karyotypes (chromosome number >50) occurred more frequently in B-lineage than in T-lineage ALL (24% vs. 4.8%). In both cell lineages deletions were mainly detected on 9p (14.1%) and 12p (8.4%), and on 6q in T-lineage ALL (4.2%). These findings were compared with loss of heterozygosity (LOH) of 6q, 9p, 11q, and 12p previously performed in 56 of the 71 patients. Among 54 sites of LOH, CGH revealed losses of the respective chromosome arms in 17 LOH-positive regions (31.5%). G-banding analysis and interphase cytogenetics with subregional probes for 14 loci confirmed the presence of genomic imbalances as detected by CGH. We, therefore, conclude that, in the absence of cytogenetic data, CGH represents a suitable method for identifying hyperdiploid karyotypes as well as prognostically relevant deletions in ALL patients.

Adolescent↗
PubMed2001

Prospective BCR-ABL analysis by polymerase chain reaction (RT-PCR) in adult acute B-lineage lymphoblastic leukemia: reliability of RT-nested-PCR and comparison to cytogenetic data.

The reliability of routine BCR-ABL RT-nested-PCR was evaluated in 1453 B-lineage ALL or hybrid leukemia at initial diagnosis by RT-nested-PCR. All BCR-ABL-positive (n = 642) and 176 BCR-ABL-negative samples underwent a second RT-PCR. In 518 patients, karyotyping and/or FISH was compared to the BCR-ABL status. The second RT-PCR revealed in 155/642 initially positive samples a divergent result (153 BCR-ABL-negative, two other transcripts) that in most cases turned out to be caused by contaminations in the first RT-nested-PCR. Confirmatory RT-PCR detected 2/176 false negative first RT-nested-PCR results. Thirty-nine specimens remained ambiguous despite different RT-PCR approaches. As far as cytogenetic evaluation and FISH is available (n = 23), the majority but not all patients with an ambiguous RT-PCR result were Ph-negative (n = 18). RT-nested-PCR and cytogenetics yielded in 346 of 383 evaluable samples a concordant result. Differing results are given and account in part to the lower sensitivity of karyotyping. Taken together, confirmed RT-PCR detected BCR-ABL fusion transcripts consistently in 487 out of 1453 ALL samples (c-ALL: 43%, pre-B ALL: 34%, pro-B ALL: 5%, B-ALL: 0%, hybrid leukemia: 5/11). Since false positive initial RT-nested-PCR data were frequent, either confirmatory second RT-PCR or FISH analysis is warranted to guarantee sensitive and reliable results of utmost clinical relevance.

Adult↗
PubMed2000

Identification of a novel putative Ran-binding protein and its close homologue.

In the process of cloning genes at the breakpoint of t(5;14) (q34;q11), a recurring translocation in acute lymphoblastic leukemia, we isolated and characterized a novel gene at 5q34, and a close human homologue (66% amino acid identity) located at 8p11-12. The presence of an importin-beta N-terminal domain at their N-terminus, their size of approximately 110 kD, their nuclear localization and the identity of the homologue to a gene of a recently submitted RanGTP binding protein (RanBP16), suggest that its protein is a novel member of the importin-beta superfamily of nuclear transport receptors, therefore called RanBP17. Northern blot analysis of human tissues revealed a ubiquitous expression pattern of the RanBP16 gene and a very restricted expression pattern of the RanBP17 gene, showing high expression in testis and pancreas. Both genes are evolutionary conserved and show a high (99 and 94%) amino acid conservation with their murine counterparts and a striking similarity (40%) to a protein product of Caenorhabditis elegans (C35A5.8).

Amino Acid Sequence↗
PubMed2000

Rapid and reliable quantification of minimal residual disease in acute lymphoblastic leukemia using rearranged immunoglobulin and T-cell receptor loci by LightCycler technology.

The detection of minimal residual disease (MRD) using immunoglobulin and T-cell receptor (TCR) rearrangements as PCR targets provides important prognostic information on the in vivo effectiveness of treatment in acute lymphoblastic leukemia (ALL). Here we report on the real-time quantification of MRD in 25 ALL patients using LightCycler technology. We designed and adapted allele-specific oligonucleotide (ASO)-PCR protocols that enabled the detection of >90% of the IGH, IGK, TCRD, and TCRG rearrangements observed in ALL patients. In all patients, at least two suitable markers could be identified (average, 3.4 markers/patient). We applied ASO-PCR with 35 immunoglobulin and TCR rearrangements (11 IGH, 6 IGK, 12 TCRG, and 6 TCRD) and compared the sensitivity and practicability of the LightCycler strategy with conventional ASO-PCR on a block thermocycler followed by quantification with gel electrophoresis. The LightCycler measured leukemia-specific PCR products at each cycle (real-time) by staining the PCR product with the DNA-binding dye SYBR Green I. LightCycler technology showed a higher sensitivity than the conventional method in eight cases, whereas the sensitivity of the other markers matched exactly. The detection level varied between 10(-4) and 10(-6) leukemic cells. Furthermore, we determined the MRD status of 27 bone marrow follow-up samples from 15 ALL patients by both methods and revealed comparable results. However, the LightCycler also allowed accurate quantification in samples containing relatively high levels (>10(-3)) of residual leukemia cells. The conventional ASO-PCR technique comprises various laborious and time-consuming PCR experiments and post-PCR steps to determine the number of cycles with the optimal linearity and sensitivity of the PCR. Real-time quantification through LightCycler technology obviates these post-PCR steps, provides the highest sensitivity via software analysis, and therefore represents a rapid, reliable, sensitive, and cost-effective technique for the routine monitoring of MRD in ALL patients.

Adult↗
PubMed2000

Concurrent activation of a novel putative transforming gene, myeov, and cyclin D1 in a subset of multiple myeloma cell lines with t(11;14)(q13;q32).

Through the application of the NIH/3T3 tumorigenicity assay to DNA from a gastric carcinoma, we have identified a novel transforming gene, designated myeov (myeloma overexpressed gene in a subset of t[11;14]-positive multiple myelomas). Sequence analyses did not reveal any homology with sequences present in the GenBank, except the deduced protein structure predicts a transmembrane localization. Myeov was mapped to chromosome 11q13 and localized by DNA fiber fluorescence in situ hybridization (FISH) 360-kilobase (kb) centromeric of cyclin D1. In 3 of 7 multiple myeloma (MM) cell lines with a t(11;14)(q13;q32) and cyclin-D1 overexpression, Northern blot analysis revealed overexpression of myeov as well. In all 7 cell lines, the translocation breakpoint was mapped within the 360-kb region between myeov and cyclin D1. DNA fiber FISH with a contig of probes covering the constant region of the immunoglobulin heavy chain (IgH) revealed that exclusively in the 3 myeov-overexpressing cell lines (KMS-12, KMS-21, and XG-5), either the 5' E(mu) enhancer or the most telomeric 3' Ealpha enhancer was juxtaposed to myeov. Although cyclin D1 overexpression represents a characteristic feature of all MM cell lines with t(11;14), our results demonstrate aberrant expression of a second putative oncogene in a subset of these cases, due to juxtaposition to IgH enhancers. The clinical relevance of this dual activation remains to be elucidated. (Blood. 2000;95:2691-2698)

Amino Acid Sequence↗
PubMed2000

Mutations of the E2F4 gene in hematological malignancies having microsatellite instability.

Mutations of coding repeats within the E2F4, TGF-betaRII, BAX, IGFIIR, and hMSH3 are critical targets of microsatellite instability (MSI) in many kinds of cancers. We analyzed 9 childhood acute lymphoblastic leukemia (ALL) samples, 5 acute myelocytic leukemia (AML) samples, and 10 adult T-cell leukemia (ATL) samples having MSI to determine whether they had mutations of the E2F4, TGF-betaRII, BAX, IGFIIR, and hMSH3 genes. Frameshift mutations were found at trinucleotide repeats within a coding exon of the E2F4 gene in 2 of 10 (20%) ATL samples and 1 of 9 (11%) childhood ALL samples. No mutations were found in the TGF-betaRII, BAX, IGFIIR, and hMSH3 genes. E2F4 is a transcription factor that influences the cell-cycle progression. These results suggest that mutations of the E2F4 gene, presumably caused by an abnormality of one of the DNA repair genes, may play an important role in development of ATL and childhood ALL. (Blood. 2000;95:1509-1510)

Adult↗
PubMed2000

Treatment of Adult ALL according to protocols of the German Multicenter Study Group for Adult ALL (GMALL).

The German Multicenter Study Group for Adult Acute Lymphoblastic leukemia (GMALL) has conducted 5 consecutive trials with more than 3000 patients since 1981. This article provides an overview on aims, treatment concepts, and results of these studies. It includes brief summaries on the development of prognostic models within the GMALL group and on approaches for prophylaxis of CNS relapse, and it summarizes specific treatment concepts for mature B-lineage acute lymphocytic leukemia.

Adolescent↗