| 1. |
- 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.
|
|
| 2. |
- Vogel, Jacob W., et al.
(författare)
-
Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
|
|
| 3. |
- Degasperi, Andrea, et al.
(författare)
-
A practical framework and online tool for mutational signature analyses show intertissue variation and driver dependencies
- 2020
-
Ingår i: Nature Cancer. - : Springer Science and Business Media LLC. - 2662-1347. ; 1:2, s. 249-263
-
Tidskriftsartikel (refereegranskat)abstract
- Mutational signatures are patterns of mutations that arise during tumorigenesis. We present an enhanced, practical framework for mutational signature analyses. Applying these methods to 3,107 whole-genome-sequenced (WGS) primary cancers of 21 organs reveals known signatures and nine previously undescribed rearrangement signatures. We highlight interorgan variability of signatures and present a way of visualizing that diversity, reinforcing our findings in an independent analysis of 3,096 WGS metastatic cancers. Signatures with a high level of genomic instability are dependent on TP53 dysregulation. We illustrate how uncertainty in mutational signature identification and assignment to samples affects tumor classification, reinforcing that using multiple orthogonal mutational signature data is not only beneficial, but is also essential for accurate tumor stratification. Finally, we present a reference web-based tool for cancer and experimentally generated mutational signatures, called Signal (https://signal.mutationalsignatures.com), that also supports performing mutational signature analyses.
|
|
| 4. |
- Jacobs, Tovia, et al.
(författare)
-
The neutrophil to lymphocyte ratio associates with markers of Alzheimer's disease pathology in cognitively unimpaired elderly people.
- 2024
-
Ingår i: Research square.
-
Tidskriftsartikel (refereegranskat)abstract
- An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally.A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β=-12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ+ (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data.We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau181 in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.
|
|
| 5. |
- Kamer, A. R., et al.
(författare)
-
Periodontal dysbiosis associates with reduced csf aβ42 in cognitively normal elderly
- 2021
-
Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Periodontal disease is a chronic, inflammatory bacterial dysbiosis that is associated with both Alzheimer’s disease (AD) and Down syndrome. Methods: A total of 48 elderly cognitively normal subjects were evaluated for differences in subgingival periodontal bacteria (assayed by 16S rRNA sequencing) between cerebrospinal fluid (CSF) biomarker groups of amyloid and neurofibrillary pathology. A dysbiotic index (DI) was defined at the genus level as the abundance ratio of known periodontal bacteria to healthy bacteria. Analysis of variance/analysis of covariance (ANOVA/ANCOVA), linear discriminant effect-size analyses (LEfSe) were used to determine the bacterial genera and species differences between the CSF biomarker groups. Results: At genera and species levels, higher subgingival periodontal dysbiosis was associated with reduced CSF amyloid beta (Aβ)42 (P = 0.02 and 0.01) but not with P-tau. Discussion: We show a selective relationship between periodontal disease bacterial dysbiosis and CSF biomarkers of amyloidosis, but not for tau. Further modeling is needed to establish the direct link between oral bacteria and Aβ. © 2021 The Authors.
|
|
| 6. |
- Li, Constance H., et al.
(författare)
-
Sex differences in oncogenic mutational processes
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.
|
|
| 7. |
- Smith, N. M., et al.
(författare)
-
Statistical Parametric Mapping in Amyloid Positron Emission Tomography
- 2022
-
Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD), the most common cause of dementia, has limited treatment options. Emerging disease modifying therapies are targeted at clearing amyloid-β (Aβ) aggregates and slowing the rate of amyloid deposition. However, amyloid burden is not routinely evaluated quantitatively for purposes of disease progression and treatment response assessment. Statistical Parametric Mapping (SPM) is a technique comparing single-subject Positron Emission Tomography (PET) to a healthy cohort that may improve quantification of amyloid burden and diagnostic performance. While primarily used in 2-[18F]-fluoro-2-deoxy-D-glucose (FDG)-PET, SPM’s utility in amyloid PET for AD diagnosis is less established and uncertainty remains regarding optimal normal database construction. Using commercially available SPM software, we created a database of 34 non-APOE ε4 carriers with normal cognitive testing (MMSE > 25) and negative cerebrospinal fluid (CSF) AD biomarkers. We compared this database to 115 cognitively normal subjects with variable AD risk factors. We hypothesized that SPM based on our database would identify more positive scans in the test cohort than the qualitatively rated [11C]-PiB PET (QR-PiB), that SPM-based interpretation would correlate better with CSF Aβ42 levels than QR-PiB, and that regional z-scores of specific brain regions known to be involved early in AD would be predictive of CSF Aβ42 levels. Fisher’s exact test and the kappa coefficient assessed the agreement between SPM, QR-PiB PET, and CSF biomarkers. Logistic regression determined if the regional z-scores predicted CSF Aβ42 levels. An optimal z-score cutoff was calculated using Youden’s index. We found SPM identified more positive scans than QR-PiB PET (19.1 vs. 9.6%) and that SPM correlated more closely with CSF Aβ42 levels than QR-PiB PET (kappa 0.13 vs. 0.06) indicating that SPM may have higher sensitivity than standard QR-PiB PET images. Regional analysis demonstrated the z-scores of the precuneus, anterior cingulate and posterior cingulate were predictive of CSF Aβ42 levels [OR (95% CI) 2.4 (1.1, 5.1) p = 0.024; 1.8 (1.1, 2.8) p = 0.020; 1.6 (1.1, 2.5) p = 0.026]. This study demonstrates the utility of using SPM with a “true normal” database and suggests that SPM enhances diagnostic performance in AD in the clinical setting through its quantitative approach, which will be increasingly important with future disease-modifying therapies.
|
|
