| 1. |
- Iacopetta, B, et al.
(författare)
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Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.
- 2006
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Ingår i: Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. - : Elsevier BV. - 0923-7534. ; 17:5, s. 842-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity. MATERIALS AND METHODS: TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation. RESULTS: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability. CONCLUSIONS: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.
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| 2. |
- Ciumas, C., et al.
(författare)
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White matter development in children with benign childhood epilepsy with centro-temporal spikes
- 2014
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 137:4, s. 1095-1106
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Tidskriftsartikel (refereegranskat)abstract
- Benign childhood epilepsy with centro-temporal spikes (BCECTS) is associated with cognitive disturbances thought to reflect interference between the epileptic focus and brain development. Using diffusion tensor imaging, Ciumas et al. demonstrate abnormal maturation of white matter at the epileptic focus, which correlates with duration of epilepsy and cognitive performance.Benign childhood epilepsy with centro-temporal spikes (BCECTS) is a unique form of non-lesional age-dependent epilepsy with rare seizures, focal electroencepalographic abnormalities affecting the same well delineated cortical region in most patients, and frequent mild to moderate cognitive dysfunctions. In this condition, it is hypothesized that interictal electroencepalographic discharges might interfere with local brain maturation, resulting in altered cognition. Diffusion tensor imaging allows testing of this hypothesis by investigating the white matter microstructure, and has previously proved sensitive to epilepsy-related alterations of fractional anisotropy and diffusivity. However, no diffusion tensor imaging study has yet been performed with a focus on BCECTS. We investigated 25 children suffering from BCECTS and 25 age-matched control subjects using diffusion tensor imaging, 3D-T-1 magnetic resonance imaging, and a battery of neuropsychological tests including Conner's scale and Wechsler Intelligence Scale for Children (fourth revision). Electroencephalography was also performed in all patients within 2 months of the magnetic resonance imaging assessment. Parametric maps of fractional anisotropy, mean-, radial-, and axial diffusivity were extracted from diffusion tensor imaging data. Patients were compared with control subjects using voxel-based statistics and family-wise error correction for multiple comparisons. Each patient was also compared to control subjects. Fractional anisotropy and diffusivity images were correlated to neuropsychological and clinical variables. Group analysis showed significantly reduced fractional anisotropy and increased diffusivity in patients compared with control subjects, predominantly over the left pre- and postcentral gyri and ipsilateral to the electroencephalographic focus. At the individual level, regions of significant differences were observed in 10 patients (40%) for anisotropy (eight reduced fractional anisotropy, one increased fractional anisotropy, one both), and 17 (56%) for diffusivity (13 increased, one reduced, three both). There were significant negative correlations between fractional anisotropy maps and duration of epilepsy in the precentral gyri, bilaterally, and in the left postcentral gyrus. Accordingly, 9 of 12 patients (75%) with duration of epilepsy > 12 months showed significantly reduced fractional anisotropy versus none of the 13 patients with duration of epilepsy 12 months. Diffusivity maps positively correlated with duration of epilepsy in the cuneus. Children with BCECTS demonstrate alterations in the microstructure of the white matter, undetectable with conventional magnetic resonance imaging, predominating over the regions displaying chronic interictal epileptiform discharges. The association observed between diffusion tensor imaging changes, duration of epilepsy and cognitive performance appears compatible with the hypothesis that interictal epileptic activity alters brain maturation, which could in turn lead to cognitive dysfunction. However, such cross-sectional association does not demonstrate causality, and other hitherto unidentified factors could represent the common cause to part or all of the observed findings.
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| 5. |
- Bottillo, Irene, et al.
(författare)
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Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours
- 2009
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 217:5, s. 693-701
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Tidskriftsartikel (refereegranskat)abstract
- Malignant peripheral nerve sheath tumours (MPNSTs) are a malignancy occurring with increased frequency in patients with neurofibromatosis type 1 (NF1). In contrast to the well-known spectrum of germline NF1 mutations, the information on somatic mutations in MPNSTs is limited. In this study, we screened NF1, KRAS, and BRAF in 47 MPNSTs from patients with (n = 25) and without (n = 22) NF1. In addition, DNA from peripheral blood and cutaneous neurofibroma biopsies from, respectively, 14/25 and 7/25 of the NF1 patients were analysed. Germline NF1 mutations were detected in ten NF1 patients, including three frameshift, three nonsense, one missense, one splicing alteration, and two large deletions. Somatic NF1 mutations were found in 10/25 (40%) NF1-associated MPNSTs, in 3/7 (43%) neurofibromas, and in 9/22 (41%) sporadic MPNSTs. Large genomic copy number changes accounted for 6/10 and 7/13 somatic mutations in NF1-associated and sporadic MPNSTs, respectively. Two NF1-associated and 13 sporadic MPNSTs did not show any NF1 mutation. A major role of the KRAS and BRAF genes was ruled out. The spectrum of germline NF1 mutations in neurofibromatosis patients with MPNST is different from the spectrum of somatic mutations seen in MPNSTs. However, the somatic events share common characteristics with the NF1-related and the sporadic tumours. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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| 6. |
- Briggs, Andrew M., et al.
(författare)
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Health systems strengthening to arrest the global disability burden : Empirical development of prioritised components for a global strategy for improving musculoskeletal health
- 2021
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Ingår i: BMJ Global Health. - : BMJ. - 2059-7908. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Despite the profound burden of disease, a strategic global response to optimise musculoskeletal (MSK) health and guide national-level health systems strengthening priorities remains absent. Auspiced by the Global Alliance for Musculoskeletal Health (G-MUSC), we aimed to empirically derive requisite priorities and components of a strategic response to guide global and national-level action on MSK health. Methods Design: mixed-methods, three-phase design. Phase 1: qualitative study with international key informants (KIs), including patient representatives and people with lived experience. KIs characterised the contemporary landscape for MSK health and priorities for a global strategic response. Phase 2: scoping review of national health policies to identify contemporary MSK policy trends and foci. Phase 3: informed by phases 1-2, was a global eDelphi where multisectoral panellists rated and iterated a framework of priorities and detailed components/actions. Results Phase 1: 31 KIs representing 25 organisations were sampled from 20 countries (40% low and middle income (LMIC)). Inductively derived themes were used to construct a logic model to underpin latter phases, consisting of five guiding principles, eight strategic priority areas and seven accelerators for action. Phase 2: of the 165 documents identified, 41 (24.8%) from 22 countries (88% high-income countries) and 2 regions met the inclusion criteria. Eight overarching policy themes, supported by 47 subthemes, were derived, aligning closely with the logic model. Phase 3: 674 panellists from 72 countries (46% LMICs) participated in round 1 and 439 (65%) in round 2 of the eDelphi. Fifty-nine components were retained with 10 (17%) identified as essential for health systems. 97.6% and 94.8% agreed or strongly agreed the framework was valuable and credible, respectively, for health systems strengthening. Conclusion An empirically derived framework, co-designed and strongly supported by multisectoral stakeholders, can now be used as a blueprint for global and country-level responses to improve MSK health and prioritise system strengthening initiatives.
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| 8. |
- Bruun, Jarle, et al.
(författare)
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Regulator of Chromosome Condensation 2 Identifies High-Risk Patients within Both Major Phenotypes of Colorectal Cancer
- 2015
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Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 21:16, s. 3759-3770
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Colorectal cancer has high incidence and mortality worldwide. Patients with microsatellite instable (MSI) tumors have significantly better prognosis than patients with microsatellite stable (MSS) tumors. Considerable variation in disease outcome remains a challenge within each subgroup, and our purpose was to identify biomarkers that improve prediction of colorectal cancer prognosis. Experimental Design: Mutation analyses of 42 MSI target genes were performed in two independent MSI tumor series (n = 209). Markers that were significantly associated with prognosis in the test series were assessed in the validation series, followed by functional and genetic explorations. The clinical potential was further investigated by immunohistochemistry in a population-based colorectal cancer series (n = 903). Results: We identified the cell-cycle gene regulator of chromosome condensation 2 (RCC2) as a cancer biomarker. We found a mutation in the 50 UTR region of RCC2 that in univariate and multivariate analyses was significantly associated with improved outcome in the MSI group. This mutation caused reduction of protein expression in dual luciferase gene reporter assays. siRNA knockdown in MSI colon cancer cells (HCT15) caused reduced cell proliferation, cell-cycle arrest, and increased apoptosis. Massive parallel sequencing revealed few RCC2 mutations in MSS tumors. However, weak RCC2 protein expression was significantly associated with poor prognosis, independent of clinical highrisk parameters, and stratifies clinically important patient subgroups with MSS tumors, including elderly patients (greater than 75 years), stage II patients, and those with rectal cancer. Conclusions: Impaired RCC2 affects functional and clinical endpoints of colorectal cancer. High-risk patients with either MSI or MSS tumors can be identified with cost-effective routine RCC2 assays. (C) 2015 AACR.
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| 9. |
- Burocziova, Monika, et al.
(författare)
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Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon
- 2019
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Ingår i: Cell Death and Disease. - : NATURE PUBLISHING GROUP. - 2041-4889. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Protein phosphatase magnesium-dependent 1 delta (PPM1D) terminates cell response to genotoxic stress by negatively regulating the tumor suppressor p53 and other targets at chromatin. Mutations in the exon 6 of the PPM1D result in production of a highly stable, C-terminally truncated PPM1D. These gain-of-function PPM1D mutations are present in various human cancers but their role in tumorigenesis remains unresolved. Here we show that truncated PPM1D impairs activation of the cell cycle checkpoints in human non-transformed RPE cells and allows proliferation in the presence of DNA damage. Next, we developed a mouse model by introducing a truncating mutation in the PPM1D locus and tested contribution of the oncogenic PPM1D(T) allele to colon tumorigenesis. We found that p53 pathway was suppressed in colon stem cells harboring PPM1D(T) resulting in proliferation advantage under genotoxic stress condition. In addition, truncated PPM1D promoted tumor growth in the colon in Apc(min) mice and diminished survival. Moreover, tumor organoids derived from colon of the Apc(min)Ppm1d(T/+) mice were less sensitive to 5-fluorouracil when compared to Apc(min)Ppm1d(+/+)and the sensitivity to 5-fluorouracil was restored by inhibition of PPM1D. Finally, we screened colorectal cancer patients and identified recurrent somatic PPM1D mutations in a fraction of colon adenocarcinomas that are p53 proficient and show defects in mismatch DNA repair. In summary, we provide the first in vivo evidence that truncated PPM1D can promote tumor growth and modulate sensitivity to chemotherapy.
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| 10. |
- Danielsen, Stine A, et al.
(författare)
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Methylated RASSF1A in malignant peripheral nerve sheath tumors identifies neurofibromatosis type 1 patients with inferior prognosis.
- 2015
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Ingår i: Neuro-Oncology. - : Oxford University Press (OUP). - 1523-5866 .- 1522-8517. ; 17:1, s. 63-69
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Tidskriftsartikel (refereegranskat)abstract
- Malignant peripheral nerve sheath tumor (MPNST) is a rare and highly aggressive disease with no evidence of effect from adjuvant therapy. It is further associated with the hereditary syndrome neurofibromatosis type 1 (NF1). Silencing of the tumor suppressor gene RASSF1A through DNA promoter hypermethylation is known to be involved in cancer development, but its impact in MPNSTs remains unsettled.
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