Dataset Information

Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

ABSTRACT: Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.

SUBMITTER: Chen CCL

PROVIDER: S-EPMC7791404 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

Chen Carol C L CCL Deshmukh Shriya S Jessa Selin S Hadjadj Djihad D Lisi Véronique V Andrade Augusto Faria AF Faury Damien D Jawhar Wajih W Dali Rola R Suzuki Hiromichi H Pathania Manav M A Deli D Dubois Frank F Woodward Eleanor E Hébert Steven S Coutelier Marie M Karamchandani Jason J Albrecht Steffen S Brandner Sebastian S De Jay Nicolas N Gayden Tenzin T Bajic Andrea A Harutyunyan Ashot S AS Marchione Dylan M DM Mikael Leonie G LG Juretic Nikoleta N Zeinieh Michele M Russo Caterina C Maestro Nicola N Bassenden Angelia V AV Hauser Peter P Virga József J Bognar Laszlo L Klekner Almos A Zapotocky Michal M Vicha Ales A Krskova Lenka L Vanova Katerina K Zamecnik Josef J Sumerauer David D Ekert Paul G PG Ziegler David S DS Ellezam Benjamin B Filbin Mariella G MG Blanchette Mathieu M Hansford Jordan R JR Khuong-Quang Dong-Anh DA Berghuis Albert M AM Weil Alexander G AG Garcia Benjamin A BA Garzia Livia L Mack Stephen C SC Beroukhim Rameen R Ligon Keith L KL Taylor Michael D MD Bandopadhayay Pratiti P Kramm Christoph C Pfister Stefan M SM Korshunov Andrey A Sturm Dominik D Jones David T W DTW Salomoni Paolo P Kleinman Claudia L CL Jabado Nada N

Cell 20201130 6

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. Th ...[more]

PMID: 33259802

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Project description:ImportanceThe D842V platelet-derived growth factor receptor α (PDGFRA) mutation identifies a molecular subgroup of gastrointestinal stromal tumors (GISTs), primarily resistant to standard tyrosine kinase inhibitors and with an overall more indolent behavior. Although functional imaging with 18F-fluorodeoxyglucose-labeled positron emission tomography ([18F]FDG-PET) plays a proven role in GISTs, especially in early assessment of tumor response, less is known about [18F]FDG uptake according to the GIST molecular subtypes.ObjectiveTo evaluate the degree of [18F]FDG uptake in PDGFRA-mutant GISTs and better define the role of functional imaging in this rare and peculiar subset of GISTs.Design, setting, and participantsThis multi-institutional retrospective cohort study involving 7 GIST reference centers in Italy included patients with PDGFRA-mutant GIST who underwent [18F]FDG-PET from January 1, 2000, to December 31, 2023. Data on the maximum standardized uptake value (SUVmax) of primary tumor or metastatic disease were collected.ExposurePDGFRA-mutant GIST and [18F]FDG-PET.Main outcome and measureThe primary outcome was the degree of [18F]FDG uptake of PDGFRA-mutant GISTs, with a focus on the D842V-mutant subgroup. Secondary objectives were to assess the association between the degree of [18F]FDG uptake and main clinicopathologic features.ResultsA total of 71 patients with PDGFRA-mutant GISTs were included in the analysis: 37 (52.1%) in the D842V subgroup (group A) and 34 (47.9%) in the non-D842V subgroup (group B). Additionally, 70 patients with KIT exon 11-mutant GIST served as a control group (group C). For all 141 participants, the median age at diagnosis was 59 (range, 26-89) years, and 81 patients (57.4%) were male. Overall, the median SUVmax was 4.4 (IQR, 0-10.1), while the median SUVmax for group A was 0 (IQR, 0-3.2); for group B, 3.6 (IQR, 0-5.1); and for group C, 10.1 (IQR, 5.1-13.9). The median SUVmax of PDGFRA-mutant GISTs was significantly lower than the median value of KIT exon 11-mutant GISTs (0 [IQR, 0-4.3] vs 10.1 [IQR, 5.1-14.0]; P < .001). Median [18F]FDG uptake was significantly lower in the D842V subgroup compared with the non-D842V subgroup (0 [IQR, 0-3.2] vs 3.6 [IQR, 0-5.1]; P = .02). Moreover, the triad of gastric primary tumor, tumor size greater than 10 cm, and SUVmax of 5.75 or less was associated with identification of PDGFRA-mutant GISTs.Conclusions and relevanceIn this cohort study of patients with PDGFRA-mutant GISTs, the D842V-mutant GISTs were associated with an overall lower [18F]FDG uptake compared with other GIST subgroups. Therefore, the role of functional imaging with [18F]FDG-PET in this subset of GISTs may be limited and should be further explored for its potential prognostic and predictive value.

Dataset Information

Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

Publications

Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

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