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- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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| 5. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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- Kuhl, I, et al.
(författare)
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POLRMT does not transcribe nuclear genes
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 514:7521, s. E7-E11
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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- Siira, SJ, et al.
(författare)
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LRPPRC-mediated folding of the mitochondrial transcriptome
- 2017
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1, s. 1532-
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Tidskriftsartikel (refereegranskat)abstract
- The expression of the compact mammalian mitochondrial genome requires transcription, RNA processing, translation and RNA decay, much like the more complex chromosomal systems, and here we use it as a model system to understand the fundamental aspects of gene expression. Here we combine RNase footprinting with PAR-CLIP at unprecedented depth to reveal the importance of RNA–protein interactions in dictating RNA folding within the mitochondrial transcriptome. We show that LRPPRC, in complex with its protein partner SLIRP, binds throughout the mitochondrial transcriptome, with a preference for mRNAs, and its loss affects the entire secondary structure and stability of the transcriptome. We demonstrate that the LRPPRC–SLIRP complex is a global RNA chaperone that stabilizes RNA structures to expose the required sites for translation, stabilization, and polyadenylation. Our findings reveal a general mechanism where extensive RNA–protein interactions ensure that RNA is accessible for its biological functions.
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| 17. |
- Terzioglu, M., et al.
(författare)
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MTERF1 Binds mtDNA to Prevent Transcriptional Interference at the Light-Strand Promoter but Is Dispensable for rRNA Gene Transcription Regulation
- 2013
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 17:4, s. 618-626
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial transcription termination factor 1, MTERF1, has been reported to couple rRNA gene transcription initiation with termination and is therefore thought to be a key regulator of mammalian mitochondrial ribosome biogenesis. The prevailing model is based on a series of observations published over the last two decades, but no in vivo evidence exists to show that MTERF1 regulates transcription of the heavy-strand region of mtDNA containing the rRNA genes. Here, we demonstrate that knockout of Mterf1 in mice has no effect on mitochondrial rRNA levels or mitochondrial translation. Instead, loss of Mterf1 influences transcription initiation at the light-strand promoter, resulting in a decrease of de novo transcription manifested as reduced 7S RNA levels. Based on these observations, we suggest that MTERF1 does not regulate heavy-strand transcription, but rather acts to block transcription on the opposite strand of mtDNA to prevent transcription interference at the light-strand promoter.
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| 18. |
- van Keulen, AM, et al.
(författare)
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Multivariable prediction model for both 90-day mortality and long-term survival for individual patients with perihilar cholangiocarcinoma: does the predicted survival justify the surgical risk?
- 2023
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 110:5, s. 599-605
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe risk of death after surgery for perihilar cholangiocarcinoma is high; nearly one in every five patients dies within 90 days after surgery. When the oncological benefit is limited, a high-risk resection may not be justified. This retrospective cohort study aimed to create two preoperative prognostic models to predict 90-day mortality and overall survival (OS) after major liver resection for perihilar cholangiocarcinoma.MethodsSeparate models were built with factors known before surgery using multivariable regression analysis for 90-day mortality and OS. Patients were categorized in three groups: favourable profile for surgical resection (90-day mortality rate below 10 per cent and predicted OS more than 3 years), unfavourable profile (90-day mortality rate above 25 per cent and/or predicted OS below 1.5 years), and an intermediate group.ResultsA total of 1673 patients were included. Independent risk factors for both 90-day mortality and OS included ASA grade III–IV, large tumour diameter, and right-sided hepatectomy. Additional risk factors for 90-day mortality were advanced age and preoperative cholangitis; those for long-term OS were high BMI, preoperative jaundice, Bismuth IV, and hepatic artery involvement. In total, 294 patients (17.6 per cent) had a favourable risk profile for surgery (90-day mortality rate 5.8 per cent and median OS 42 months), 271 patients (16.2 per cent) an unfavourable risk profile (90-day mortality rate 26.8 per cent and median OS 16 months), and 1108 patients (66.2 per cent) an intermediate risk profile (90-day mortality rate 12.5 per cent and median OS 27 months).ConclusionPreoperative risk models for 90-day mortality and OS can help identify patients with resectable perihilar cholangiocarcinoma who are unlikely to benefit from surgical resection. Tailored shared decision-making is particularly essential for the large intermediate group.
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