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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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- van der Ende, EL, et al.
(författare)
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Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia
- 2020
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 91:6, s. 612-621
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Tidskriftsartikel (refereegranskat)abstract
- Synapse dysfunction is emerging as an early pathological event in frontotemporal dementia (FTD), however biomarkers are lacking. We aimed to investigate the value of cerebrospinal fluid (CSF) neuronal pentraxins (NPTXs), a family of proteins involved in homeostatic synapse plasticity, as novel biomarkers in genetic FTD.MethodsWe included 106 presymptomatic and 54 symptomatic carriers of a pathogenic mutation in GRN, C9orf72 or MAPT, and 70 healthy non-carriers participating in the Genetic Frontotemporal dementia Initiative (GENFI), all of whom had at least one CSF sample. We measured CSF concentrations of NPTX2 using an in-house ELISA, and NPTX1 and NPTX receptor (NPTXR) by Western blot. We correlated NPTX2 with corresponding clinical and neuroimaging datasets as well as with CSF neurofilament light chain (NfL) using linear regression analyses.ResultsSymptomatic mutation carriers had lower NPTX2 concentrations (median 643 pg/mL, IQR (301–872)) than presymptomatic carriers (1003 pg/mL (624–1358), p<0.001) and non-carriers (990 pg/mL (597–1373), p<0.001) (corrected for age). Similar results were found for NPTX1 and NPTXR. Among mutation carriers, NPTX2 concentration correlated with several clinical disease severity measures, NfL and grey matter volume of the frontal, temporal and parietal lobes, insula and whole brain. NPTX2 predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale plus FTD modules. In longitudinal CSF samples, available in 13 subjects, NPTX2 decreased around symptom onset and in the symptomatic stage.DiscussionWe conclude that NPTX2 is a promising synapse-derived disease progression biomarker in genetic FTD.
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