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- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)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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- Gerstung, M, et al.
(author)
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Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes
- 2015
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 5901-
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Journal article (peer-reviewed)abstract
- Cancer is a genetic disease, but two patients rarely have identical genotypes. Similarly, patients differ in their clinicopathological parameters, but how genotypic and phenotypic heterogeneity are interconnected is not well understood. Here we build statistical models to disentangle the effect of 12 recurrently mutated genes and 4 cytogenetic alterations on gene expression, diagnostic clinical variables and outcome in 124 patients with myelodysplastic syndromes. Overall, one or more genetic lesions correlate with expression levels of ~20% of all genes, explaining 20–65% of observed expression variability. Differential expression patterns vary between mutations and reflect the underlying biology, such as aberrant polycomb repression for ASXL1 and EZH2 mutations or perturbed gene dosage for copy-number changes. In predicting survival, genomic, transcriptomic and diagnostic clinical variables all have utility, with the largest contribution from the transcriptome. Similar observations are made on the TCGA acute myeloid leukaemia cohort, confirming the general trends reported here.
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- Herman, Zachary J, et al.
(author)
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Outcomes of bone-patellar tendon-bone autograft and quadriceps tendon autograft for ACL reconstruction in an all-female soccer player cohort with mean 4.8-year follow up.
- 2024
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In: Journal of ISAKOS : joint disorders & orthopaedic sports medicine. - 2059-7762. ; 9:1, s. 34-38
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Journal article (peer-reviewed)abstract
- The purpose is to compare functional outcomes, return to soccer rates, and revision rates in an all-female soccer player cohort undergoing quadriceps tendon (QT) autograft ACLR versus bone-patellar tendon-bone (BPTB) autograft ACLR.Female soccer players who sustained an ACL rupture and underwent primary anatomic, single-bundle ACLR with BPTB autograft or QT autograft were included. Demographic and surgical characteristics were collected. Outcomes of interest included Tegner score, International Knee Documentation Committee (IKDC) score, Marx score, return to soccer rates, and failure rates.Data on 23 patients undergoing BPTB autograft ACLR and 14 undergoing QT autograft ACLR was available. Average age was 18.7 years, and average follow up was 4.8 years. Overall, 76% (28/37) returned to soccer and 5.4% (2/37) underwent revision ACLR. No major significant differences were found in demographic or surgical characteristics. No differences were found in postoperative IKDC scores, preoperative, postoperative, or change from pre-to postoperative Marx activity scores, or pre-and postoperative Tegner scores between the groups. QT autograft ACLR patients had significantly less change in Tegner scores pre-to postoperatively compared to the BTPB autograft ACLR group (0.6±1.2 versus 2.1±1.8; p=0.02). Both groups had similar rates of return to soccer [78% (18/23) BPTB autograft ACLR versus 71% (10/14) QT autograft ACLR; p=0.64] and rates of revision (8.7 % (2/23) BPTB autograft ACLR; 0 % (0/14) QT autograft ACLR.Results of this study suggest that BPTB autograft ACLR and QT autograft ACLR produce comparable, successful functional and return to soccer outcomes in this all-female soccer player cohort study. Larger, prospective studies are needed to improve the strength of conclusions and provide more information on the optimal graft choice for female soccer players. Surgeons can use the results of this study to counsel female soccer players on expected outcomes after ACLR.III.
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- Meredith, Sean J., et al.
(author)
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Return to Sport After Anterior Cruciate Ligament Injury: Panther Symposium ACL Injury Return to Sport Consensus Group
- 2020
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In: Orthopaedic Journal of Sports Medicine. - : SAGE Publications. - 2325-9671. ; 8:6
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Journal article (peer-reviewed)abstract
- Background: A precise and consistent definition of return to sport (RTS) after anterior cruciate ligament (ACL) injury is lacking, and there is controversy surrounding the process of returning patients to sport and their previous activity level. Purpose: The aim of the Panther Symposium ACL Injury Return to Sport Consensus Group was to provide a clear definition of RTS after ACL injury and a description of the RTS continuum as well as provide clinical guidance on RTS testing and decision-making. Study Design: Consensus statement. Methods: An international, multidisciplinary group of ACL experts convened as part of a consensus meeting. Consensus statements were developed using a modified Delphi method. Literature review was performed to report the supporting evidence. Results: Key points include that RTS is characterized by achievement of the preinjury level of sport and involves a criteria-based progression from return to participation to RTS and, ultimately, return to performance. Purely time-based RTS decision-making should be abandoned. Progression occurs along an RTS continuum, with decision-making by a multidisciplinary group that incorporates objective physical examination data and validated and peer-reviewed RTS tests, which should involve functional assessment as well as psychological readiness. Consideration should be given to biological healing, contextual factors, and concomitant injuries. Conclusion: The resultant consensus statements and scientific rationale aim to inform the reader of the complex process of RTS after ACL injury that occurs along a dynamic continuum. Research is needed to determine the ideal RTS test battery, the best implementation of psychological readiness testing, and methods for the biological assessment of healing and recovery.
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