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- Parris, Toshima Z, 1978, et al.
(författare)
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Genome-wide multi-omics profiling of the 8p11-p12 amplicon in breast carcinoma.
- 2018
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:35, s. 24140-24154
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Tidskriftsartikel (refereegranskat)abstract
- Genomic instability contributes to the neoplastic phenotype by deregulating key cancer-related genes, which in turn can have a detrimental effect on patient outcome. DNA amplification of the 8p11-p12 genomic region has clinical and biological implications in multiple malignancies, including breast carcinoma where the amplicon has been associated with tumor progression and poor prognosis. However, oncogenes driving increased cancer-related death and recurrent genetic features associated with the 8p11-p12 amplicon remain to be identified. In this study, DNA copy number and transcriptome profiling data for 229 primary invasive breast carcinomas (corresponding to 185 patients) were evaluated in conjunction with clinicopathological features to identify putative oncogenes in 8p11-p12 amplified samples. Illumina paired-end whole transcriptome sequencing and whole-genome SNP genotyping were subsequently performed on 23 samples showing high-level regional 8p11-p12 amplification to characterize recurrent genetic variants (SNPs and indels), expressed gene fusions, gene expression profiles and allelic imbalances. We now show previously undescribed chromothripsis-like patterns spanning the 8p11-p12 genomic region and allele-specific DNA amplification events. In addition, recurrent amplification-specific genetic features were identified, including genetic variants in the HIST1H1E and UQCRHL genes and fusion transcripts containing MALAT1 non-coding RNA, which is known to be a prognostic indicator for breast cancer and stimulated by estrogen. In summary, these findings highlight novel candidate targets for improved treatment of 8p11-p12 amplified breast carcinomas.
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| 2. |
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| 3. |
- Truvé, Katarina, et al.
(författare)
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Identification of candidate genetic variants and altered protein expression in neural stem and mature neural cells support altered microtubule function to be an essential component in bipolar disorder
- 2020
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Identification of causative genetic variants leading to the development of bipolar disorder (BD) could result in genetic tests that would facilitate diagnosis. A better understanding of affected genes and pathways is also necessary for targeting of genes that may improve treatment strategies. To date several susceptibility genes have been reported from genome-wide association studies (GWAS), but little is known about specific variants that affect disease development. Here, we performed quantitative proteomics and whole-genome sequencing (WGS). Quantitative proteomics revealed NLRP2 as the most significantly up-regulated protein in neural stem cells and mature neural cells obtained from BD-patient cell samples. These results are in concordance with our previously published transcriptome analysis. Furthermore, the levels of FEZ2 and CADM2 proteins were also significantly differentially expressed in BD compared to control derived cells. The levels of FEZ2 were significantly downregulated in neural stem cells (NSC) while CADM2 was significantly up-regulated in mature neuronal cell culture. Promising novel candidate mutations were identified in the ANK3, NEK3, NEK7, TUBB, ANKRD1, and BRD2 genes. A literature search of candidate variants and deregulated proteins revealed that there are several connections to microtubule function for the molecules putatively involved. Microtubule function in neurons is critical for axon structure and axonal transport. A functional dynamic microtubule is also needed for an advocate response to cellular and environmental stress. If microtubule dynamics is compromised by mutations, it could be followed by deregulated expression forming a possible explanation for the inherited vulnerability to stressful life events that have been proposed to trigger mood episodes in BD patients.
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| 4. |
- Vizlin-Hodzic, Dzeneta, et al.
(författare)
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Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages
- 2017
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Neuro-inflammation and neuronal communication are considered as mis-regulated processes in the aetiology and pathology of bipolar disorder (BD). Which and when specific signal pathways become abnormal during the ontogeny of bipolar disorder patients is unknown. To address this question, we applied induced pluripotent stem cell (iPSC) technology followed by cortical neural differentiation on adipocyte-derived cells from BD type I patients (with psychotic episodes in psychiatric history) and healthy volunteers (controls). RNA sequencing in iPSC and cortical neural stem cell (NSC) lines were used to examine alterations between the transcriptomes from BD I and control samples during transition from the pluripotent stage towards the neural developmental stage. At the iPSC stage, the most highly significant differentially expressed gene (DEG) was the NLRP2 inflammasome (P = 2.66 × 10-10). Also among 42 DEGs at the NSC stage, NLRP2 showed the strongest statistical significance (P = 3.07 × 10-19). In addition, we have also identified several cytoskeleton-associated genes as DEGs from the NSC stage, such as TMP2, TAGLN, and ACTA2; the former two genes are recognised for the first time to be associated with BD. Our results also suggest that iPSC-derived BD-cortical NSCs carry several abnormalities in dopamine and GABA receptor canonical pathways, underlining that our in vitro BD model reflects pathology in the CNS. This would indicate that mis-regulated gene expression of inflammatory, neurotransmitter, and cytoskeletal signalling occurs during early foetal brain development of BD I patients.
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