| 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. |
|
|
| 3. |
|
|
| 4. |
- Herbst, SA, et al.
(författare)
-
Proteogenomics refines the molecular classification of chronic lymphocytic leukemia
- 2022
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 6226-
-
Tidskriftsartikel (refereegranskat)abstract
- Cancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic-based diagnostics. The relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities such as chronic lymphocytic leukemia (CLL). Here, we characterize the proteome and transcriptome alongside genetic and ex-vivo drug response profiling in a clinically annotated CLL discovery cohort (n = 68). Unsupervised clustering of the proteome data reveals six subgroups. Five of these proteomic groups are associated with genetic features, while one group is only detectable at the proteome level. This new group is characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B cell receptor signaling protein abundances (ASB-CLL). Classifiers developed to identify ASB-CLL based on its characteristic proteome or splicing signature in two independent cohorts (n = 165, n = 169) confirm that ASB-CLL comprises about 20% of CLL patients. The inferior overall survival in ASB-CLL is also independent of both TP53- and IGHV mutation status. Our multi-omics analysis refines the classification of CLL and highlights the potential of proteomics to improve cancer patient stratification beyond genetic and transcriptomic profiling.
|
|
| 5. |
- Northcott, Paul A, et al.
(författare)
-
Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
- 2014
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 511:7510, s. 428-428
-
Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
|
|
| 6. |
- Voronina, N, et al.
(författare)
-
The age of adult pilocytic astrocytoma cells
- 2021
-
Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 40:16, s. 2830-2841
-
Tidskriftsartikel (refereegranskat)abstract
- Adult pilocytic astrocytomas (PAs) have been regarded as indistinguishable from pediatric PAs in terms of genome-wide expression and methylation patterns. It has been unclear whether adult PAs arise early in life and remain asymptomatic until adulthood, or whether they develop during adulthood. We sought to determine the age and origin of adult human PAs using two types of “marks” in the genomic DNA. First, we analyzed the DNA methylation patterns of adult and pediatric PAs to distinguish between PAs of different anatomic locations (n = 257 PA and control brain tissues). Second, we measured the concentration of nuclear bomb test-derived 14C in genomic DNA (n = 14 cases), which indicates the time point of the formation of human cell populations. Our data suggest that adult and pediatric PAs developing in the infratentorial brain are closely related and potentially develop from precursor cells early in life, whereas supratentorial PAs might show age and location-specific differences.
|
|
| 7. |
- Bejanin, J. H., et al.
(författare)
-
Three-Dimensional Wiring for Extensible Quantum Computing: The Quantum Socket
- 2016
-
Ingår i: Physical Review Applied. - 2331-7019. ; 6:4
-
Tidskriftsartikel (refereegranskat)abstract
- Quantum computing architectures are on the verge of scalability, a key requirement for the implementation of a universal quantum computer. The next stage in this quest is the realization of quantum error-correction codes, which will mitigate the impact of faulty quantum information on a quantum computer. Architectures with ten or more quantum bits (qubits) have been realized using trapped ions and superconducting circuits. While these implementations are potentially scalable, true scalability will require systems engineering to combine quantum and classical hardware. One technology demanding imminent efforts is the realization of a suitable wiring method for the control and the measurement of a large number of qubits. In this work, we introduce an interconnect solution for solid-state qubits: the quantum socket. The quantum socket fully exploits the third dimension to connect classical electronics to qubits with higher density and better performance than two-dimensional methods based on wire bonding. The quantum socket is based on spring-mounted microwires-the three-dimensional wires-that push directly on a microfabricated chip, making electrical contact. A small wire cross section (approximately 1 mm), nearly nonmagnetic components, and functionality at low temperatures make the quantum socket ideal for operating solid-state qubits. The wires have a coaxial geometry and operate over a frequency range from dc to 8 GHz, with a contact resistance of approximately 150 m Omega, an impedance mismatch of approximately 10 Omega, and minimal cross talk. As a proof of principle, we fabricate and use a quantum socket to measure high-quality superconducting resonators at a temperature of approximately 10 mK. Quantum error-correction codes such as the surface code will largely benefit from the quantum socket, which will make it possible to address qubits located on a two-dimensional lattice. The present implementation of the socket could be readily extended to accommodate a quantum processor with a (10 x 10)-qubit lattice, which would allow for the realization of a simple quantum memory.
|
|
