| 1. |
- 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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| 2. |
- Gerstung, M, et al.
(författare)
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The evolutionary history of 2,658 cancers
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 122-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
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| 3. |
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| 4. |
- Steele, Christopher D, et al.
(författare)
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Signatures of copy number alterations in human cancer
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 606:7916, s. 984-991
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Tidskriftsartikel (refereegranskat)abstract
- Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage-fusion-bridge cycles, among others, which may lead to chromosomal instability and aneuploidy1,2. These copy number alterations contribute to cancer initiation, progression and therapeutic resistance3-5. Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing 33 human cancer types from The Cancer Genome Atlas6 revealed a set of 21 copy number signatures that explain the copy number patterns of 97% of samples. Seventeen copy number signatures were attributed to biological phenomena of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, chromothripsis and haploidization. The aetiologies of four copy number signatures remain unexplained. Some cancer types harbour amplicon signatures associated with extrachromosomal DNA, disease-specific survival and proto-oncogene gains such as MDM2. In contrast to base-scale mutational signatures, no copy number signature was associated with many known exogenous cancer risk factors. Our results synthesize the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes that give rise to these alterations.
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| 5. |
- Yabroudi, M. A., et al.
(författare)
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Predictors of Revision Surgery After Primary Anterior Cruciate Ligament Reconstruction
- 2016
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Ingår i: Orthopaedic Journal of Sports Medicine. - : SAGE Publications. - 2325-9671. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Revision anterior cruciate ligament (ACL) reconstruction surgery occurs in 5% to 15% of individuals undergoing ACL reconstruction. Identifying predictors for revision ACL surgery is of essence in the pursuit of creating adequate prevention programs and to identify individuals at risk for reinjury and revision. Purpose: To determine predictors of revision ACL surgery after failed primary ACL reconstruction. Methods: A total of 251 participants (mean age SD, 26.1 9.9 years) who had undergone primary ACL reconstruction 1 to 5 years earlier completed a comprehensive survey to determine predictors of revision ACL surgery at a mean 3.4 +/- 1.3 years after the primary ACL reconstruction. Potential predictors that were assessed included subject characteristics (age at the time of surgery, time from injury to surgery, sex, body mass index, preinjury activity level, return to sport status), details of the initial injury (mechanism; concomitant injury to other ligaments, menisci, and cartilage), surgical details of the primary reconstruction (Lachman and pivot shift tests under anesthesia, graft type, femoral drilling technique, reconstruction technique), and postoperative course (length of rehabilitation, complications). Univariate and multivariate logistic regression analyses were performed to identify factors that predicted the need for revision ACL surgery. Results: Overall, 21 (8.4%) subjects underwent revision ACL surgery. Univariate analysis showed that younger age at the time of surgery (P = .003), participation in sports at a competitive level (P = .023), and double-bundle ACL reconstruction (P = .024) predicted increased risk of revision ACL surgery. Allograft reconstructions also demonstrated a trend toward greater risk of revision ACL surgery (P = .076). No other variables were significantly associated with revision ACL surgery. Multivariate analysis revealed that revision ACL surgery was only predicted by age at the time of surgery and graft type (autograft vs allograft). Conclusion: The overall revision ACL surgery rate after primary unilateral ACL reconstruction was 8.4%. Univariate predictors of revision ACL reconstruction included younger age at the time of surgery, competitive baseline activity level, and double-bundle ACL reconstruction. However, multivariable logistic regression analysis indicated that age and reconstruction performed with allograft were the only independent predictors of revision ACL reconstruction.
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