| 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. |
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| 3. |
- Jaffee, E. M., et al.
(författare)
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Future cancer research priorities in the USA: a Lancet Oncology Commission
- 2017
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Ingår i: Lancet Oncology. - 1470-2045. ; 18:11, s. E653-E706
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Forskningsöversikt (refereegranskat)abstract
- We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$ 2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control.
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| 4. |
- Zaidi, Syed H., et al.
(författare)
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Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival
- 2020
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR=0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR=1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features. Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds.
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| 5. |
- Rashid, S. J., et al.
(författare)
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Modelling of single-crystal diamond Schottky diodes for high-voltage applications
- 2006
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Ingår i: Diamond and related materials. - : Elsevier BV. - 0925-9635 .- 1879-0062. ; 15, s. 317-323
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Tidskriftsartikel (refereegranskat)abstract
- The modelling of Schottky m-i-p(+) (SMIP) diodes fabricated on chemical vapour deposited (CVD) single crystal (SC) diamond intrinsic layers grown on highly boron doped CVD diamond Substrates is reported. Variations in intrinsic layer thickness, Schottky metal type and operating temperature have been included in the analysis. Numerical models that take into account the activation of dopants, concentration and temperature dependant mobility and avalanche coefficients have been derived to successfully simulate experimental diamond devices.
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| 6. |
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| 7. |
- Rashid, S. J., et al.
(författare)
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Numerical Parameterization of Chemical-Vapor-Deposited (CVD) Single-Crystal Diamond for Device Simulation and Analysis
- 2008
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Ingår i: IEEE Transactions on Electron Devices. - 0018-9383 .- 1557-9646. ; 55:10, s. 2744-2756
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Tidskriftsartikel (refereegranskat)abstract
- High-quality electronic-grade intrinsic chemical-vapor-deposited (CVD) single-crystal diamond layers having exceptionally high carrier mobilities have been reported by Isberg et al. This makes the realization of novel electronic devices in diamond, particularly for high-voltage and high-temperature applications, a viable proposition. As such, material models which can capture the particular features of diamond as a semiconductor are required to analyze, optimize, and quantitatively design new devices. For example, the incomplete ionization of boron in diamond and the transition to metallic conduction in heavily boron-doped layers require accurate carrier freeze-out models to be included in the simulation of diamond devices. Models describing these phenomena are proposed in this paper and include numerical approximation of intrinsic diamond which is necessary to formulate doping- and temperature-dependent mobility models. They enable a concise numerical description of single-crystal diamond which agrees with data obtained from material characterization. The models are verified by application to new Schottky m-i-p(+) diode structures in diamond. Simulated forward characteristics show excellent correlation with experimental measurements. In spite of the lack of impact ionization data for single-crystal diamond, approximation of avalanche coefficient parameters from other wide-bandgap semiconductors has also enabled the reverse blocking characteristics of diamond diodes to be simulated. Acceptable agreement with breakdown voltage from experimental devices made with presently available single-crystal CVD diamond is obtained.
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| 8. |
- Barretina, Jordi, et al.
(författare)
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Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.
- 2010
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:8, s. 715-21
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Tidskriftsartikel (refereegranskat)abstract
- Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.
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| 9. |
- Haq, Rizwan, et al.
(författare)
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BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition
- 2013
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:11, s. 4321-4326
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Tidskriftsartikel (refereegranskat)abstract
- Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in similar to 30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy.
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| 10. |
- Li, Constance H., et al.
(författare)
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Sex differences in oncogenic mutational processes
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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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.
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