| 1. |
- Bleeker, Gitta, et al.
(författare)
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MIBG scans in patients with stage 4 neuroblastoma reveal two metastatic patterns, one is associated with MYCN amplification and in MYCN-amplified tumours correlates with a better prognosis
- 2015
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 42:2, s. 222-230
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The aim of this study was to find clinically relevant MIBG-avid metastatic patterns in patients with newly diagnosed stage 4 neuroblastoma. Methods Diagnostic I-123-MIBG scans from 249 patients (123 from a European and 126 from the COG cohort) were assessed for metastatic spread in 14 body segments and the form of the lesions: "focal" (clear margins distinguishable from adjacent background) or "diffuse" (indistinct margins, dispersed throughout the body segment). The total numbers of diffuse and focal lesions were recorded. Patients were then categorized as having lesions exclusively focal, lesions more focal than diffuse, lesions more diffuse than focal, or lesions exclusively diffuse. Results Diffuse lesions affected a median of seven body segments and focal lesions a median of two body segments (P<0.001, both cohorts). Patients with a focal pattern had a median of 2 affected body segments and those with a diffuse pattern a median of 11 affected body segments (P<0.001, both cohorts). Thus, two MIBG-avid metastatic patterns emerged: "limited-focal" and "extensive-diffuse". The median numbers of affected body segments in MYCN-amplified (MNA) tumours were 5 (European cohort) and 4 (COG cohort) compared to 9 and 11, respectively, in single-copy MYCN (MYCNsc) tumours (P<0.001). Patients with exclusively focal metastases were more likely to have a MNA tumour (60 % and 70 %, respectively) than patients with the other types of metastases (23 % and 28 %, respectively; P<0.001). In a multivariate Cox regression analysis, focal metastases were associated with a better event-free and overall survival than the other types of metastases in patients with MNA tumours in the COG cohort (P<0.01). Conclusion Two metastatic patterns were found: a " limited and focal" pattern found mainly in patients with MNA neuroblastoma that correlated with prognosis, and an " extensive and diffuse" pattern found mainly in patients with MYCNsc neuroblastoma.
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| 2. |
- Claeys, Shana, et al.
(författare)
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ALK positively regulates MYCN activity through repression of HBP1 expression
- 2019
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 38:15, s. 2690-2705
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Tidskriftsartikel (refereegranskat)abstract
- ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor entity will be essential. We show that mutant ALK downregulates the ‘HMG-box transcription factor 1’ (HBP1) through the PI3K-AKT–FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17~92. Combined targeting of HBP1 by PI3K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.
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| 3. |
- Holmquist Mengelbier, Linda, et al.
(författare)
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Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer.
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P=0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.
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| 4. |
- von Stedingk, Kristoffer, et al.
(författare)
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Individual patient risk stratification of high-risk neuroblastomas using a two-gene score suited for clinical use.
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 137:4, s. 868-877
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Tidskriftsartikel (refereegranskat)abstract
- Several gene expression-based prognostic signatures have been described in neuroblastoma, but none have successfully been applied in the clinic. Here we have developed a clinically applicable prognostic gene signature, both with regards to number of genes and analysis platform. Importantly, it does not require comparison between patients and is applicable amongst high-risk patients. The signature is based on a two-gene score (R-score) with prognostic power in high-stage tumours (stage 4 and/or MYCN-amplified diagnosed after 18 months of age). QPCR-based and array-based analyses of matched cDNAs confirmed cross platform (array-qPCR) transferability. We also defined a fixed cut-off value identifying prognostically differing subsets of high-risk patients on an individual patient basis. This gene expression signature independently contributes to the current neuroblastoma classification system, and if prospectively validated could provide further stratification of high-risk patients, and potential upfront identification of a group of patients that are in need of new/additional treatment regimens.
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