| 1. |
- Boj, Sylvia F, et al.
(author)
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Organoid models of human and mouse ductal pancreatic cancer
- 2015
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In: Cell. - : Cell press. - 0092-8674 .- 1097-4172. ; 160:1-2, s. 324-338
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Journal article (peer-reviewed)abstract
- Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.
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| 2. |
- Cuppen, Edwin, et al.
(author)
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Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care
- 2022
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In: JCO Precision Oncology. - : American Society of Clinical Oncology. - 2473-4284. ; 6
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Journal article (peer-reviewed)abstract
- PURPOSE The combination of whole-genome and transcriptome sequencing (WGTS) is expected to transformdiagnosis and treatment for patients with cancer. WGTS is a comprehensive precision diagnostic test that isstarting to replace the standard of care for oncology molecular testing in health care systems around the world;however, the implementation and widescale adoption of this best-in-class testing is lacking.METHODS Here, we address the barriers in integrating WGTS for cancer diagnostics and treatment selection andanswer questions regarding utility in different cancer types, cost-effectiveness and affordability, and otherpractical considerations for WGTS implementation.RESULTS We review the current studies implementing WGTS in health care systems and provide a synopsis of theclinical evidence and insights into practical considerations for WGTS implementation. We reflect on regulatory,costs, reimbursement, and incidental findings aspects of this test.CONCLUSION WGTS is an appropriate comprehensive clinical test for many tumor types and can replacemultiple, cascade testing approaches currently performed. Decreasing sequencing cost, increasing number ofclinically relevant aberrations and discovery of more complex biomarkers of treatment response, should pave theway for health care systems and laboratories in implementing WGTS into clinical practice, to transform diagnosisand treatment for patients with cancer.
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| 3. |
- Jiao, Wei, et al.
(author)
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A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Journal article (peer-reviewed)abstract
- In cancer, the primary tumour's organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor samples and 88% and 83% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA.
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| 4. |
- Ressa, Anna, et al.
(author)
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A System-wide Approach to Monitor Responses to Synergistic BRAF and EGFR Inhibition in Colorectal Cancer Cells
- 2018
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In: Molecular & Cellular Proteomics. - : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. - 1535-9476 .- 1535-9484. ; 17:10, s. 1892-1908
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Journal article (peer-reviewed)abstract
- Intrinsic and/or acquired resistance represents one of the great challenges in targeted cancer therapy. A deeper understanding of the molecular biology of cancer has resulted in more efficient strategies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has also been observed in colorectal cancer patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block intrinsic resistance to BRAF inhibitors. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant colorectal cancer cells as a model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both known and novel responses. We primarily observe widespread up-regulation of receptor tyrosine kinases and metabolic pathways upon BRAF inhibition. These findings point to mechanisms by which the drug-treated cells switch energy sources and enter a quiescent-like state as a defensive response, while additionally compensating for the MAPK pathway inhibition.
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| 5. |
- Riba, Michela, et al.
(author)
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The 1+Million Genomes Minimal Dataset for Cancer
- 2024
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In: Nature Genetics. - 1061-4036. ; 56:5, s. 733-736
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Journal article (peer-reviewed)abstract
- Defining minimal standards for data collection is key to creating interoperative, searchable genomic and clinical databases. We highlight here the 1+Million Genomes Minimal Dataset for Cancer, encompassing 140 items in 8 domains to foster the collection of cancer data, inform transnational cooperation and advance precision cancer medicine.
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| 6. |
- Scheffer, Marten, et al.
(author)
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The Evolution of Functionally Redundant Species; Evidence from Beetles
- 2015
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In: PLOS ONE. - [Scheffer, Marten; Vergnon, Remi; van Nes, Egbert H.; Cuppen, Jan G. M.; Peeters, Edwin T. H. M.] geningen Univ, Dept Aquat Ecol & Water Qual Management, NL-6700 AA Wageningen, Netherlands. [Leijs, Remko] S Australian Museum, Adelaide, SA 5000, Australia. [Leijs, Remko] Univ Adelaide, Sch Earth & Environm Sci, Adelaide, SA, Australia. [Leijs, Remko] Flinders Univ South Australia, Sch Biol Sci, Adelaide, SA, Australia. [Nilsson, Anders N.] Umea Univ, Dept Ecol & Environm Sci, S-90187 Umea, Sweden. : Public Library of Science (PLoS). - 1932-6203. ; 10:10
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Journal article (peer-reviewed)abstract
- While species fulfill many different roles in ecosystems, it has been suggested that numerous species might actually share the same function in a near neutral way. So-far, however, it is unclear whether such functional redundancy really exists. We scrutinize this question using extensive data on the world's 4168 species of diving beetles. We show that across the globe these animals have evolved towards a small number of regularly-spaced body sizes, and that locally co-existing species are either very similar in size or differ by at least 35%. Surprisingly, intermediate size differences (10-20%) are rare. As body-size strongly reflects functional aspects such as the food that these generalist predators can eat, these beetles thus form relatively distinct groups of functional look-a-likes. The striking global regularity of these patterns support the idea that a self-organizing process drives such species-rich groups to self-organize evolutionary into clusters where functional redundancy ensures resilience through an insurance effect.
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| 7. |
- van Es, Michael A, et al.
(author)
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Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis
- 2011
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In: Annals of Neurology. - : Wiley-Blackwell. - 0364-5134 .- 1531-8249. ; 70:6, s. 964-973
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios.RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD.INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.
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