| 1. |
|
|
| 2. |
- Campbell, PJ, et al.
(författare)
-
Pan-cancer analysis of whole genomes
- 2020
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
-
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.
|
|
| 3. |
- Convery, RS, et al.
(författare)
-
Abnormal pain perception is associated with thalamo-cortico-striatal atrophy in C9orf72 expansion carriers in the GENFI cohort
- 2020
-
Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 91:12, s. 1325-1328
-
Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is typically associated with changes in behaviour, language and movement. However, recent studies have shown that patients can also develop an abnormal response to pain, either heightened or diminished. We aimed to investigate this symptom in mutation carriers within the Genetic FTD Initiative (GENFI).MethodsAbnormal responsiveness to pain was measured in 462 GENFI participants: 281 mutation carriers and 181 mutation-negative controls. Changes in responsiveness to pain were scored as absent (0), questionable or very mild (0.5), mild (1), moderate (2) or severe (3). Mutation carriers were classified into C9orf72 (104), GRN (128) and MAPT (49) groups, and into presymptomatic and symptomatic stages. An ordinal logistic regression model was used to compare groups, adjusting for age and sex. Voxel-based morphometry was performed to identify neuroanatomical correlates of abnormal pain perception.ResultsAltered responsiveness to pain was present to a significantly greater extent in symptomatic C9orf72 expansion carriers than in controls: mean score 0.40 (SD 0.71) vs 0.00 (0.04), reported in 29% vs 1%. No significant differences were seen between the other symptomatic groups and controls, or any of the presymptomatic mutation carriers and controls. Neural correlates of altered pain perception in C9orf72 expansion carriers were the bilateral thalamus and striatum as well as a predominantly right-sided network of regions involving the orbitofrontal cortex, inferomedial temporal lobe and cerebellum.ConclusionChanges in pain perception are a feature of C9orf72 expansion carriers, likely representing a disruption in somatosensory, homeostatic and semantic processing, underpinned by atrophy in a thalamo-cortico-striatal network.
|
|
| 4. |
|
|
| 5. |
- Gao, YX, et al.
(författare)
-
Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis
- 2020
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 12184-
-
Tidskriftsartikel (refereegranskat)abstract
- We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Samra, K, et al.
(författare)
-
Genetic forms of primary progressive aphasia within the GENetic Frontotemporal dementia Initiative (GENFI) cohort: comparison with sporadic primary progressive aphasia
- 2023
-
Ingår i: Brain communications. - : Oxford University Press (OUP). - 2632-1297. ; 5:2, s. fcad036-
-
Tidskriftsartikel (refereegranskat)abstract
- Primary progressive aphasia is most commonly a sporadic disorder, but in some cases, it can be genetic. This study aimed to understand the clinical, cognitive and imaging phenotype of the genetic forms of primary progressive aphasia in comparison to the canonical nonfluent, semantic and logopenic subtypes seen in sporadic disease. Participants with genetic primary progressive aphasia were recruited from the international multicentre GENetic Frontotemporal dementia Initiative study and compared with healthy controls as well as a cohort of people with sporadic primary progressive aphasia. Symptoms were assessed using the GENetic Frontotemporal dementia Initiative language, behavioural, neuropsychiatric and motor scales. Participants also underwent a cognitive assessment and 3 T volumetric T1-weighted MRI. One C9orf72 (2%), 1 MAPT (6%) and 17 GRN (44%) symptomatic mutation carriers had a diagnosis of primary progressive aphasia. In the GRN cohort, 47% had a diagnosis of nonfluent variant primary progressive aphasia, and 53% had a primary progressive aphasia syndrome that did not fit diagnostic criteria for any of the three subtypes, called primary progressive aphasia-not otherwise specified here. The phenotype of the genetic nonfluent variant primary progressive aphasia group largely overlapped with that of sporadic nonfluent variant primary progressive aphasia, although the presence of an associated atypical parkinsonian syndrome was characteristic of sporadic and not genetic disease. The primary progressive aphasia -not otherwise specified group however was distinct from the sporadic subtypes with impaired grammar/syntax in the presence of relatively intact articulation, alongside other linguistic deficits. The pattern of atrophy seen on MRI in the genetic nonfluent variant primary progressive aphasia group overlapped with that of the sporadic nonfluent variant primary progressive aphasia cohort, although with more posterior cortical involvement, whilst the primary progressive aphasia-not otherwise specified group was strikingly asymmetrical with involvement particularly of the insula and dorsolateral prefrontal cortex but also atrophy of the orbitofrontal cortex and the medial temporal lobes. Whilst there are overlapping symptoms between genetic and sporadic primary progressive aphasia syndromes, there are also distinct features. Future iterations of the primary progressive aphasia consensus criteria should encompass such information with further research needed to understand the earliest features of these disorders, particularly during the prodromal period of genetic disease.
|
|
| 10. |
|
|
