Biomedical subjects

Susann Fält

Publications and source records attributed to Susann Fält.

6 recordsLinked to original sources

PubMed2006

Rad51-related changes in global gene expression.

High expression of Rad51, the catalytic component in homologous recombination, has been reported to contribute to genomic instability. To elucidate biological processes related to Rad51, we performed global gene expression analysis on human fibrosarcoma cells induced to express variable Rad51 levels. The results indicate that Rad51 overexpression mediates late rather than early transcriptional responses. Using Gene Ontology analysis, we extracted functional annotations for Rad51-related changes in gene expression that were independent of general cell culture effects. High Rad51 levels conferred increased expression of genes involved in actin remodelling. These changes were accompanied by alterations in cell morphology. Moreover, core components of the mismatch repair (MMR) machinery were down-regulated in response to increased Rad51 expression. Given the role of MMR in the correction of DNA mismatches during replication and recombination, a concurrent increase in Rad51 levels and decrease in the expression of MMR genes could conceivably act synergistically towards genomic instability.

Actins↗

PubMed2005

Distinctive gene expression pattern in VH3-21 utilizing B-cell chronic lymphocytic leukemia.

The usage of the immunoglobulin (Ig) V(H)3-21 gene is associated with poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) despite V(H) gene mutation status. Many V(H)3-21+ patients also display restricted heavy- and light-chain Ig gene rearrangements, implying a role of antigen selection in disease development. To explore the specific phenotypic/genotypic features among V(H)3-21+ B-CLLs, we compared gene expression patterns in 15 V(H)3-21+ and 24 non-V(H)3-21 patients (11 with unmutated and 13 with mutated V(H) genes) using Affymetrix microarray analysis (approximately 12,500 genes). A distinct expression profile was identified for V(H)3-21+ patients in contrast to the Ig-unmutated and -mutated groups. By applying different algorithms, the data enabled an efficient class discrimination of the V(H)3-21+ subset based on 27 or 57 genes. A set of genes was sorted out which, using different analytical methods, consistently gave a distinction between V(H)3-21+ and non-V(H)3-21 samples. Several of these genes are involved in regulation of DNA replication/cell-cycle control, transcription and protein kinase activity, which may render the V(H)3-21+ cells with a higher proliferative drive. However, no clear evidence of increased B-cell receptor signaling was found in the V(H)3-21+ group. Altogether, our identification of a specific V(H)3-21 profile may provide insights into the pathogenesis of the V(H)3-21+ subgroup.

Aged↗

PubMed2005

Identification of progression markers in B-CLL by gene expression profiling.

OBJECTIVE: B-cell chronic lymphocytic leukemia is a heterogeneous disease with a pronounced variation in the clinical course. With the purpose of identifying genes that could be related to disease progression, we have performed gene expression profiling on B-CLL patients with an indolent disease and patients with a progressive disease with need for therapy. MATERIALS AND METHODS: we applied the Affymetrix GeneChip technique to 11 B-CLL patients with stable and 10 patients with clinically progressive disease. Supervised and unsupervised clustering methods with different algorithms were used to identify genes that tend to give a distinction between stable and progressive disease. RESULTS: The supervised learning procedures identified groups of genes with a combined power to discriminate samples from progressive and stable disease with 70-90% accuracy. The gene for protein phosphatase 2 regulatory subunit B' (B56) gamma isoform (PPP2R5C) and the gene for retinoblastoma-like 2 (p130) (RBL2) were included among the best discriminators; both genes were downregulated in progressive as compared to stable B-CLL. In a hierarchical clustering analysis based on gene expression pattern three clinical subcategories could be identified: one with a more severe clinical outcome, a second one with good prognosis, and a third one that was intermediate between the other two groups. CONCLUSIONS: Our application of microarray analysis on a clinically well defined material has identified a number of genes with combined expression patterns related to stable or progressive disease in general. Unsupervised clustering suggested the existence of subclasses of samples in the progressive group that may be identifiable through gene expression patterns.

Aged↗

PubMed2003

Long-term global gene expression patterns in irradiated human lymphocytes.

Radiation-induced chromosomal instability has many features in common with genomic instability of cancer cells. In order to understand the delayed cellular response to ionizing radiation we have studied variations in the patterns of gene expression in primary human lymphocytes at various time points after gamma irradiation in vitro. Cells either exposed to 3 Gy of gamma rays in vitro or unexposed were subjected to long-term growth in bulk culture or as individual T-cell clones. Samples were taken at days 7, 17 or 55 from bulk cultures. The T-cell clones were harvested after 22-46 days. Total RNA was used to generate cDNA probes for hybridization to oligonucleotide arrays containing 12,625 gene templates (Affymetrix). The results showed that: (i) irradiation as well as culture time influence the gene expression patterns, (ii) the number of genes with increased or decreased expression in irradiated cells increases dramatically with increasing culture time, (iii) the changes of gene expression showed a significantly more diversified pattern in the irradiated T-cell clones than in non-irradiated clones. We conclude that the diversification of the transcriptome associated with radiation exposure reflects subtle changes of expression in many genes, rather than being the result of major changes in a few genes. Finally, (iv) we sorted out a set of genes whose change of expression correlates with radiation exposure in both bulk cultures and T-cell clones. Very few of these genes overlap with genes that change during the acute response to radiation. This set of genes may be regarded as a starting point for further studies of the cellular phenotype associated with radiation-induced genomic instability.

Cells, Cultured↗

PubMed2003

Influence of common XPD and XRCC1 variant alleles on p53 mutations in lung tumors.

The DNA repair proteins XPD and XRCC1 are involved in the nucleotide and base excision repair of DNA lesions induced by many tobacco and environmental carcinogens. Common variant alleles at the XPD (312Asn, 751Gln) and XRCC1 (399Gln) loci have been identified and associated with increased risk for lung cancer. We therefore investigated a possible effect of these variant alleles on the frequency and spectrum of p53 mutations in the tumors of 97 Swedish lung cancer patients (56 never-smokers and 41 age-, gender-, and hospital-matched ever-smokers). The p53 gene was mutated in 4 never-smokers (7%) and 11 ever-smokers (27%). Smoking-related transversion-type mutations predominated over transitions among smokers (8:3), but not among never-smokers (1:3). None of the variant alleles altered the overall frequency of p53 mutation. Transversions, however, were marginally increased among patients with at least one XPD variant allele compared with patients who were wild-type homozygotes (73% vs. 25% for the Asp312Asn polymorphism, P = 0.095; 78% vs. 33% for Lys751Gln, P = 0.085). Five of six women or six of seven smokers who carried at least one XPD 751Gln allele had p53 transversion. The XRCC1 variant allele did not show any effect on the p53 mutation. We conclude that the XPD variant alleles may be associated with an increased frequency of smoking-related p53 mutations in lung tumors, presumably due to reduced DNA repair proficiency.

Adenocarcinoma↗

PubMed2002

The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk.

The DNA repair protein xeroderma pigmentosum complementation group D (XPD) is involved in the nucleotide excision repair of DNA lesions induced by many tobacco and environmental carcinogens. In order to study the functional impact of the common polymorphisms in XPD exon 10 (G > A, Asp312Asn) and exon 23 (A > C, Lys751Gln), we have genotyped 185 Swedish lung cancer cases (97 smokers and 88 never-smokers) and 162 matched population controls (83 smokers and 79 never-smokers). Presence of one or two variant alleles was associated with increased risk for lung cancer among never-smokers only, in particular younger (<70 years) never-smokers [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.1-6.5 for exon 10; OR = 3.2, 95% CI = 1.3-8.0 for exon 23, adjusted for age, gender and environmental tobacco smoke]. Aromatic DNA adduct level (AL) in peripheral lymphocytes was found to be similar between cases and controls, but significantly increased by current or recent smoking. Overall, there was a significant trend for increasing AL with increasing number of variant alleles in exon 10 (P = 0.02) or in exon 23 (P = 0.001). In addition, subjects with the combined exon 10 AA and exon 23 CC genotype showed a significantly higher AL compared with all those with any of the other genotypes (P = 0.02). We conclude that the XPD variant alleles may be associated with reduced repair of aromatic DNA adducts in general and increased lung cancer risk among never-smokers.

Adenocarcinoma↗