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- Arbajian, Elsa, et al.
(författare)
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Methylation patterns and chromatin accessibility in neuroendocrine lung cancer
- 2020
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:8, s. 1-17
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Tidskriftsartikel (refereegranskat)abstract
- Lung cancer is the worldwide leading cause of death from cancer. Epigenetic modifications such as methylation and changes in chromatin accessibility are major gene regulatory mechanisms involved in tumorigenesis and cellular lineage commitment. We aimed to characterize these processes in the context of neuroendocrine (NE) lung cancer. Illumina 450K DNA methylation data were collected for 1407 lung cancers including 27 NE tumors. NE differentially methylated regions (NE-DMRs) were identified and correlated with gene expression data for 151 lung cancers and 31 human tissue entities from the Genotype-Tissue Expression (GTEx) consortium. Assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were performed on eight lung cancer cell lines, including three NE cell lines, to identify neuroendocrine specific gene regulatory elements. We identified DMRs with methylation patterns associated with differential gene expression and an NE tumor phenotype. DMR-associated genes could further be split into six functional modules, including one highly specific gene module for NE lung cancer showing high expression in both normal and malignant brain tissue. The regulatory potential of NE-DMRs was further validated in vitro using paired ATAC-and RNA-seq and revealed both proximal and distal regulatory elements of canonical NE-marker genes such as CHGA, NCAM1, INSM1, as well as a number of novel candidate markers of NE lung cancer. Using multilevel genomic analyses of both tumor bulk tissue and lung cancer cell lines, we identified a large catalogue of gene regulatory elements related to the NE phenotype of lung cancer.
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| 2. |
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| 3. |
- Davidsson, Josef, et al.
(författare)
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Array based characterization of a terminal deletion involving chromosome subband 15q26.2: an emerging syndrome associated with growth retardation, cardiac defects and developmental delay.
- 2008
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Subtelomeric regions are gene rich and deletions in these chromosomal segments have been demonstrated to account for approximately 2.5% of patients displaying mental retardation with or without association of dysmorphic features. However, cases that report de novo terminal deletions on chromosome arm 15q are rare. METHODS: In this study we present the first example of a detailed molecular genetic mapping of a de novo deletion in involving 15q26.2-qter, caused by the formation of a dicentric chromosome 15, using metaphase FISH and tiling resolution (32 k) genome-wide array-based comparative genomic hybridization (CGH). RESULTS: After an initial characterization of the dicentric chromosome by metaphase FISH, array CGH analysis mapped the terminal deletion to encompass a 6.48 megabase (Mb) region, ranging from 93.86-100.34 Mb on chromosome 15. CONCLUSION: In conclusion, we present an additional case to the growing family of reported cases with 15q26-deletion, thoroughly characterized at the molecular cytogenetic level. In the deleted regions, four candidate genes responsible for the phenotype of the patient could be delineated: IGFR1, MEF2A, CHSY1, and TM2D3. Further characterization of additional patients harboring similar 15q-aberrations might hopefully in the future lead to the description of a clear cut clinically recognizable syndrome.
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| 4. |
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| 5. |
- Davidsson, Josef, et al.
(författare)
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Array-based genotype-phenotype correlation in a case of supernumerary ring chromosome 12
- 2008
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163. ; 73:1, s. 44-49
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Tidskriftsartikel (refereegranskat)abstract
- Supernumerary ring chromosomes (SRC) account for approximately 10% of prenatal marker chromosomes and 60% of these SRCs are associated with an abnormal phenotype of the patient carrying them. SRCs have, with few exceptions, not been characterized at the molecular genetic level. Here, we present the first case of a SRC 12 thoroughly investigated with tiling resolution array-based comparative genomic hybridization (array CGH); multicolor, centromere, subtelomeric and whole chromosome painting fluorescence in situ hybridization. In addition, to be able to correlate phenotypic manifestations with a possible pathogenetic outcome of the SRC 12, we retrospectively compared and reviewed all 14 cases of SRC 12 reported, including our present case. Our analyses revealed that the SRC comprised 25.53-46.40 Mb of chromosome 12, a region known to harbor 47 annotated genes of which nine were of putative pathogenetic relevance. Reviewing the previously described cases of SRC 12, we could not establish any specific recurrent features associated with this type of SRC. This most probably reflects heterogeneity in break-point distribution among the reported cases, resulting in differently sized ring chromosomes and hence varying phenotypic traits of the patients. Detailed genomic evaluation, by array CGH or similar techniques may thus be of importance to predict the clinical course in individual cases.
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| 6. |
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| 7. |
- Davidsson, Josef, et al.
(författare)
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Constitutional trisomy 8 mosaicism as a model for epigenetic studies of aneuploidy.
- 2013
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Ingår i: Epigenetics & Chromatin. - : Springer Science and Business Media LLC. - 1756-8935. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- To investigate epigenetic patterns associated with aneuploidy we used constitutional trisomy 8 mosaicism (CT8M) as a model, enabling analyses of single cell clones, harboring either trisomy or disomy 8, from the same patient; this circumvents any bias introduced by using cells from unrelated, healthy individuals as controls. We profiled gene and miRNA expression as well as genome-wide and promoter specific DNA methylation and hydroxymethylation patterns in trisomic and disomic fibroblasts, using microarrays and methylated DNA immunoprecipitation.
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| 8. |
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| 9. |
- Davidsson, Josef, et al.
(författare)
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Deletion of the SCN gene cluster on 2q24.4 is associated with severe epilepsy: An array-based genotype-phenotype correlation and a comprehensive review of previously published cases.
- 2008
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Ingår i: Epilepsy Research. - : Elsevier BV. - 1872-6844 .- 0920-1211. ; Jun 6, s. 69-79
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To characterize a deletion of chromosome 2q at the molecular level in a patient suffering from severe epilepsy resembling severe myoclonic epilepsy of infancy/Dravet's syndrome (SMEI/DS) and to correlate other cases harboring deletions in the same region to morphological and clinical data. METHODS: Array-based comparative genomic hybridization (array CGH) was performed on DNA from the patient. Forty-three previously published cases reporting deletions within region 2q21-q31 were collected and analyzed regarding their cytogenetic and clinical data. RESULTS: A del(2)(q24.3q31.1) was detected in the patient, spanning a 10.4-megabase (Mb) region between 165.18 and 175.58Mb, harboring 47 genes. FISH analysis was performed, confirming this deletion. Twenty-two of the 43 previously published cases were seizure-positive. The most common dysmorphic features were ear abnormalities, microcephaly, micrognathia and brachysyndactyly for all patients as well as for solely the seizure-positive and -negative ones. For the 22 seizure-positive cases chromosome subband 2q24.3 constituted the smallest commonly deleted region among the majority of the cases, where subbands 2q22.1 and 2q33.3 represented the most proximal and distal breakpoint, respectively. CONCLUSIONS: Based on the early age of presentation and the severity of the epilepsy reported for the majority of the seizure-positive cases it was concluded that SMEI/DS could be the epileptic encephalopathy associated with deletions within the 2q22.1-q33.3 region, due to haploinsuffiency of SCN1A and/or complete or partial deletion of other voltage-gated sodium channel genes caused by the aberration. Furthermore, our study supports that array CGH is a competent technique for screening SCN1A mutation-negative patients diagnosed with SMEI/DS-like epilepsies and dysmorphic features, generating rapid and high-resolution data of genomic imbalances present in the patients.
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| 10. |
- Davidsson, Josef, et al.
(författare)
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dup(19)(q12q13.2): Array-based Genotype-Phenotype Correlation of a New Possibly Obesity-related Syndrome.
- 2010
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Ingår i: Obesity. - : Wiley. - 1930-739X .- 1930-7381. ; 18, s. 580-587
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Tidskriftsartikel (refereegranskat)abstract
- Small supernumerary marker chromosomes (sSMCs) derived from the near-centromeric area of chromosome 2 are very rare. In addition, duplications of the 2p11.2-->q11.2 region have displayed considerable variability between patients harboring and lacking clinical findings. Moreover, constitutional duplication of the 19q12-->q13.2 region has previously only been described in two cases and was associated with delay of developmental milestones, corpus callosum anomalies, and obesity. Herein, we present a genotype-phenotype correlation in a patient harboring two sSMCs derived from chromosomes 2 and 14 or 22, respectively. The DNA was studied using G-banding, fluorescence in situ hybridization techniques, and array-based comparative genomic hybridization. A 48,XX,+der(2)del(2)(p11)del(2)(q11.2),+der(14)t(14;19)(q11;q12)del(19)(q13.31) or 48,XX,+der(2)del(2)(p11)del(2)(q11.2),+der(22)t(22;19)(q11;q12)del(19)(q13.31) was detected in the patient. The sSMC 14;19 or 22;19, with its centromere originating from either chromosome 14 or 22, encompassed a 13.56 megabase (Mb) 19q derived region, harboring 263 genes, and the sSMC 2 a 2.71 Mb region including 29 genes. The patient had symptoms including a ventral septal defect, bilateral grade IV urinary reflux, corpus callosum agenesis, microphthalmia, and obesity. The 19q segment contained the genes AKT2, CEACAM1, CEBPA, LIPE, and TGFB1 which are involved in adipose tissue homeostasis and insulin resistance, and could potentially contribute to the obese phenotype observed. Array-based genetic characterization and long-term clinical evaluation with attention toward weight gain in patients with chromosome 19q duplications might in the future lead to the description of a obesity-associated genetic syndrome, something that could have implications in management and treatment of patients carrying a dup(19)(q12q13.2). Whether the der(2)(p11q11.2) contributes to the phenotype remains inconclusive.
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