| 1. |
- Keck, Michaela Kristina, et al.
(författare)
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Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification
- 2023
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 145:1, s. 49-69
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Tidskriftsartikel (refereegranskat)abstract
- Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0–14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.
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| 2. |
- Trouillas, Jacqueline, et al.
(författare)
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Are aggressive pituitary tumors and carcinomas two sides of the same coin? Pathologists reply to clinician’s questions
- 2020
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Ingår i: Reviews in Endocrine and Metabolic Disorders. - : Springer Science and Business Media LLC. - 1389-9155 .- 1573-2606. ; 21:2, s. 243-251
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Forskningsöversikt (refereegranskat)abstract
- Pituitary adenohypophyseal tumors are considered as benign and termed “adenomas”. However, many tumors are invasive and a proportion of these exhibit an “aggressive behavior” with premature death due to progressive growth. Only very rare (0.2%) tumors with metastases are considered malignant and termed “carcinomas”. Taking into account this variability in behavior and the oncological definition, pathologists have proposed changing the term adenoma to tumor. Here we explain why use the term tumor instead of adenoma and identify tumor characteristics, associated with a high risk for poor prognosis. In a cohort of 125 tumors with aggressive behavior (APT) and 40 carcinomas with metastases (PC), clinical and pathological features were very similar. The comparison of this cohort (APT+PC) with a reference surgical cohort of 374 unselected patients clearly shows that the two cohorts differ greatly, especially the percentage of tumors with Ki67 ≥ 10% (35%vs3%; p < 0.001). A five-tiered prognostic classification, associating invasion and proliferation, identified grade 2b tumors (invasive and proliferative), with a high risk of recurrence/progression. Because half of the APT+ PC tumors have a Ki67 index ≥10%, and 80% of them show 2 or 3 positive markers of proliferation, we suggest that tumors that are clinically aggressive, invasive and highly proliferative with a Ki67 ≥ 10%, represent tumors with malignant potential. The percentage of grade 2b tumors, suspected of malignancy, which will become aggressive tumors or carcinomas is unknown. It is probably very low, but higher than 0.2% in surgical series. Early identification and active treatment of these aggressive tumors is needed to decrease morbidity and prolong survival.
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| 3. |
- Zhukova, Nataliya, et al.
(författare)
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WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma
- 2014
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of gammaH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
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