| 1. |
- Buckley, Patrick G, et al.
(författare)
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A full-coverage, high-resolution human chromosome 22 genomic microarrayfor clinical and research applications
- 2002
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 11:25, s. 3221-3229
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Tidskriftsartikel (refereegranskat)abstract
- We have constructed the first comprehensive microarray representing a human chromosome for analysis of DNA copy number variation. This chromosome 22 array covers 34.7 Mb, representing 1.1% of the genome, with an average resolution of 75 kb. To demonstrate the utility of the array, we have applied it to profile acral melanoma, dermatofibrosarcoma, DiGeorge syndrome and neurofibromatosis 2. We accurately diagnosed homozygous/heterozygous deletions, amplifications/gains, IGLV/IGLC locus instability, and breakpoints of an imbalanced translocation. We further identified the 14-3-3 eta isoform as a candidate tumor suppressor in glioblastoma. Two significant methodological advances in array construction were also developed and validated. These include a strictly sequence defined, repeat-free, and non-redundant strategy for array preparation. This approach allows an increase in array resolution and analysis of any locus; disregarding common repeats, genomic clone availability and sequence redundancy. In addition, we report that the application of phi29 DNA polymerase is advantageous in microarray preparation. A broad spectrum of issues in medical research and diagnostics can be approached using the array. This well annotated and gene-rich autosome contains numerous uncharacterized disease genes. It is therefore crucial to associate these genes to specific 22q-related conditions and this array will be instrumental towards this goal. Furthermore, comprehensive epigenetic profiling of 22q-located genes and high-resolution analysis of replication timing across the entire chromosome can be studied using our array.
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| 2. |
- Flordal Thelander, Emma, et al.
(författare)
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Detailed assessment of copy number alterations revealing homozygous deletions in 1p and 13q in mantle cell lymphoma
- 2007
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Ingår i: Leukemia Research. - : Elsevier BV. - 0145-2126 .- 1873-5835. ; 31:9, s. 1219-1230
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) is characterized by over-expression of cyclin Dl as a result of the characteristic t(11;14)(q13;q32). However, this translocation alone has proven not to be sufficient for lymphomagenesis, suggesting the involvement of additional alterations. We have characterized 35 cases of MCL by array comparative genomic hybridization with an average resolution of 0.97Mb distributed over the complete human genome. The most common alterations were losses in 1p13.2–p31.1, 6q16.2–q27, 8p21.3, 9p13.2–p24.3, 9q13–q31.3, 11q14.3–q23.3, 13q14.13–q21.31, 13q33.1–q34, and 22q11.23–q13.33 and gains involving 3q21.2–q29, 7p12.1–p22.3, 8q24.13–q24.23, and 18q21.33–q22.3. Four homozygous deletions were identified in totally three patients; two overlapping at 1p32.3, and two adjacent at 13q32.3. The homozygous deletions at 1p32.3 cover the CDKN2C locus (coding for p18), while the region at 13q32.3 does not encompass any known tumor suppressor genes. A gain in 3q was significantly associated with shorter survival (P=0.047).
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| 3. |
- Ichimura, Koichi
(författare)
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Cell cycle regulatory genes in human astrocytic tumors
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is a genetic disorder of somatic cells. Neoplastic transformation and malignant progression may be a consequence of accumulated multiple genetic changes in a cell. Astrocytic gliomas are the commonest brain tumors in humans. They are subclassified into different malignancy grades, and malignant progression of astrocytomas (malignancy grade II) to anaplastic astrocytomas (malignancy grade III) and glioblastomas (malignancy grade IV) is a well-documented phenomenon. The aim of the study described in this thesis was to improve and extend the characterization of the genetic changes associated with the oncogenesis and progression of astrocytic gliomas and to identify some genes involved in these processes. The areas of the genome studied primarily included 9p and 12q. The findings in these regions led to the identification and detailed study of cell cycle regulatory gene alterations in gliomas. Homozygous deletion of the interferon a (IFNA) locus, located at 9p22, was known to occur frequently in glioblastomas. In order to investigate whether IFNA is the real target of such deletions, precise deletion mapping around the IFNA locus was carried out combining RFLP analysis, densitometry and microsatellite analysis in astrocyticgliomas of different malignancy grades. The commonly deleted region was defined asbeing between and not including the IFNA and D9S171 loci, suggesting the loss of an asyet unidentified tumor suppressor gene. The CDKN2A (p161MTSl) and CDKN2B (p151MTS2) genes, coding for inhibitors of the Cyclin D/CDK4 complex, were identified and localized within this region by others. A more detailed allelic assessment of the region in our tumors showed that the frequency of homozygous deletion was the highest at the CDKN2A locus. Approximately 40% of all glioblastomas had homozygous deletions and an additional 30% had hemizygous deletions of the CDKN2A gene with anaplastic astrocytomas showing a similar pattern but at lower frequencies. The homozygous and hemizygous deletions involved both CDKN2A and CDKN2B genes in the vast majority of tumors. Hemizygous deletions of the CDKN2A were infrequently associated with mutations, a total of five being identified among 14 anaplastic astrocytomas and 39 glioblastomas. No mutations of CDKN2B were identified. Variable expression of CDKN2A was documented in cases retaining at least one allele. Hypermethylation of the 5'CpG islands of CDKN2A did not correlate with a lack of gene expression. In parallel with this study, a mapping of the MDM2 amplicon on 12ql3-14 in gliomas was carried out. CDK4 and SAS, not MDM2, were identified as being most frequently amplified. Amplification of all these three genes, but not other co-amplified genes, was invariably accompanied by overexpression of transcripts. When the data from 9p and 12q were compiled, amplification of CDK4 was preferentially found among glioblastomas and anaplastic astrocytomas without CDKN2A deletions. Normally CDK4 forms a kinase complex with Cyclin Dl and phosphorylates pRB in the G, phase of the cell cycle. Phosphorylated pRB releases the E2F transcription factors which transcriptionally activate the genes required for S phase entry and DNA replication. The protein product of CDKN2A, p 16, is a specific inhibitor of Cyclin D/CDK4 kinase complex. Thus alteration of one of these genes, involved in the same cell-cycle regulatory pathway was shown to be a common abnormality in anaplastic astrocytomas and glioblastomas. In order to obtain further evidence to support the hypothesis that alteration of cell cycle regulatory genes plays an important role in astrocytic tumor progression, the RBI gene was examined in the same tumors. A total lack of wild-type RBI was observed preferentially among tumors with normal CDKN2A and CDK4. In total, 64% of glioblastomas contained either no wild-type type CDKN2A or RBI, or had amplification of CDK4. Only 6% retained two, apparently wild-type, copies of these genes. Astrocytoma grade II had no amplification of CDK4 and always retained one wild-type allele of CDKN2A and RBI. Our results implicate CDKN2A, CDK4 and RBI in their progression and malignant progression. Alterations of G,/S phase cell cycle regulation appeared to be a cardinal mechanism in the development and progression of human anaplastic astrocytomas and glioblastomas.
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| 4. |
- Kwiecinska, Anna, et al.
(författare)
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Amplification of 2p as a Genomic Marker for Transformation in Lymphoma
- 2014
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 53:9, s. 750-768
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Tidskriftsartikel (refereegranskat)abstract
- To outline further genetic mechanisms of transformation from follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL), we have performed whole genome array-CGH in 81 tumors from 60 patients [29 de novo DLBCL (dnDLBCL), 31 transformed DLBCL (tDLBCL), and 21 antecedent FL]. In 15 patients, paired tumor samples (primary FL and a subsequent tDLBCL) were available, among which three possessed more than two subsequent tumors, allowing us to follow specific genetic alterations acquired before, during, and after the transformation. Gain of 2p15-16.1 encompassing, among others, the REL, BCL11A, USP34, COMMD1, and OTX1 genes was found to be more common in the tDLBCL compared with dnDLBCL (P < 0.001). Furthermore, a high-level amplification of 2p15-16.1 was also detected in the FL stage prior to transformation, indicating its importance during the transformation event. Quantitative real-time PCR showed a higher level of amplification of REL, USP34, and COMMD1 (all involved in the NF kappa B-pathway) compared with BCL11A, which indicates that the altered genes disrupting the NF kappa B pathway may be the driver genes of transformation rather than the previously suggested BCL11A. Moreover, a 17q21.33 amplification was exclusively found in tDLBCL, never in FL (P < 0.04) or dnDLBCL, indicating an upregulation of genes of importance during the later phase of transformation. Taken together, our study demonstrates potential genomic markers for disease progression to clinically more aggressive forms. We also confirm the importance of the TP53-, CDKN2A-, and NF kappa B-pathways for the transformation from FL to DLBCL.
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| 5. |
- Thelander, Emma Flordal, et al.
(författare)
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Characterization of 6q deletions in mature B cell lymphomas and childhood acute lymphoblastic leukemia
- 2008
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 49:3, s. 477-487
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Tidskriftsartikel (refereegranskat)abstract
- The study was undertaken with the aim to outline deletion patterns involving the long arm of chromosome 6, a common abnormality in lymphoproliferative disorders. Using a chromosome 6 specific tile path array, 60 samples from in total 49 cases with mantle cell lymphoma (MCL), de novo diffuse large B-cell lymphoma (DLBCL), transformed DLBCL as well as preceding follicular lymphoma (FL), and childhood acute lymphoblastic leukemia (ALL), were characterized. Twenty-six of the studied cases, representing all diagnoses, showed a 6q deletion among which 85% involved a 3Mb region in 6q21. The minimal deleted interval in 6q21 encompasses the FOXO3A, PRDM1 and HACE1 candidate genes. The PRDM1 gene was found homozygously deleted in a case of DLBCL. Moreover, in two DLBCL cases, an overlapping homozygous deletion was identified in 6q23.3-24.1, encompassing the TNFAIP3 gene among others. Taken together, we refined the deletion pattern within the long arm of chromosome 6 in four different types of hematological malignances, suggesting the location of tumor suppressor genes involved in the tumor progression.
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