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- 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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| 4. |
- Colo, GP, et al.
(författare)
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Focal adhesion disassembly is regulated by a RIAM to MEK-1 pathway
- 2012
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Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 125:22Pt 22, s. 5338-5352
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Tidskriftsartikel (refereegranskat)abstract
- Cell migration and invasion require regulated turnover of integrin-dependent adhesion complexes. RIAM is an adaptor protein mediating talin recruitment to the cell membrane, whose depletion leads to defective melanoma cell migration and invasion. Here we investigated the potential involvement of RIAM in focal adhesion (FA) dynamics. RIAM-depleted melanoma and breast carcinoma cells displayed an increased number, size and stability of FAs, which accumulated centrally located at the ventral cell surface, a phenotype caused by defective FA disassembly. Impairment in FA disassembly due to RIAM knocking down correlated with deficient integrin-dependent MEK-Erk1/2 activation, and importantly, overexpression of constitutively active MEK resulted in rescue of FA disassembly and recovery of cell invasion. Furthermore, RIAM-promoted RhoA activation following integrin engagement was needed for subsequent Erk1/2 activation, and RhoA overexpression partially rescued the FA phenotype in RIAM-depleted cells, suggesting a functional role also for RhoA downstream of RIAM, but upstream of Erk1/2. In addition, RIAM knock down led to enhanced phosphorylation of paxillin Tyr118 and Tyr31. However, expression of phosphomimetic and non-phosphorylatable mutants at these paxillin residues indicated that paxillin hyper-phosphorylation is a subsequent consequence of the blockade of FA disassembly, but does not cause the FA phenotype. RIAM depletion also weakened association between FA proteins, suggesting that it may play important adaptor roles for the correct assembly of adhesion complexes. Our data indicate that integrin-triggered, RIAM-dependent MEK activation may represent a key feed-back event required for efficient FA disassembly, which may contribute to explain the role of RIAM in cell migration and invasion.
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