Targeted Next-Generation Sequencing Reveals Divergent Clonal Evolution in Components of Composite Pleomorphic Xanthoastrocytoma-Ganglioglioma

Lucas, Calixto-Hope G; Davidson, Christian; Alashari, Mouied; Putnam, Angelica R.; Whipple, Nicholas; Bruggers, Carol S.; Mendez, Joe; Cheshier, Samuel; Walker, Jeffrey B; Ramani, Biswarathan; Cadwell, Cathryn R.; Sullivan, Daniel V; Lu, Rufei; Mirchia, Kanish; Ziffle, Jessica Van; Devine, Patrick; Goldschmidt, Ezequiel; Hervey-Jumper, Shawn L.; Gupta, Nalin; Bush, Nancy Ann Oberheim; Raleigh, David R.; Bollen, Andrew W.; Tihan, Tarık; Pekmezci, Melike; Perry, Arie

doi:10.1093/jnen/nlac044

Cited by 6 publications

(7 citation statements)

References 21 publications

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“…2). Several publications also describe composite tumors of variable entities, most often including GG and PXA, a feature in need of further and systematic molecular-genetic exploration in the LEAT cohort [24,38].…”

Section: Discussionmentioning

confidence: 99%

Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes

et al. 2023

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Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.

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Section: Discussionmentioning

confidence: 99%

Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes

et al. 2023

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“…Notably, both components of these tumours were positive for BRAF V600E, whereas selectively in the PXA component, a homozygous CDKN2A/B deletion/p16 loss and a higher number of chromosomal aberrations were obvious. Hence, these composite tumours were suggested to represent a stage of progression from GG to PXA [48,49]. Further, more comprehensive analyses like whole-genome or proteomic approaches may serve to further address this issue and to clarify whether this also applies for tumours designated as aGG.…”

Section: Discussionmentioning

confidence: 99%

Anaplastic ganglioglioma—A diagnosis comprising several distinct tumour types

Reinhardt

Pfister

Schrimpf

et al. 2022

Neuropathology Appl Neurobio

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Aims Anaplastic ganglioglioma is a rare tumour, and diagnosis has been based on histological criteria. The 5th edition of the World Health Organization Classification of Tumours of the Central Nervous System (CNS WHO) does not list anaplastic ganglioglioma as a distinct diagnosis due to lack of molecular data in previous publications. We retrospectively compiled a cohort of 54 histologically diagnosed anaplastic gangliogliomas to explore whether the molecular profiles of these tumours represent a separate type or resolve into other entities. Methods Samples were subjected to histological review, desoxyribonucleic acid (DNA) methylation profiling and next‐generation sequencing. Morphological and molecular data were summarised to an integrated diagnosis. Results The majority of tumours designated as anaplastic gangliogliomas resolved into other CNS WHO diagnoses, most commonly pleomorphic xanthoastrocytoma (16/54), glioblastoma, isocitrate dehydrogenase protein (IDH) wild type and diffuse paediatric‐type high‐grade glioma, H3 wild type and IDH wild type (11 and 2/54), followed by low‐grade glial or glioneuronal tumours including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumour and diffuse leptomeningeal glioneuronal tumour (5/54), IDH mutant astrocytoma (4/54) and others (6/54). A subset of tumours (10/54) was not assignable to a CNS WHO diagnosis, and common molecular profiles pointing to a separate entity were not evident. Conclusions In summary, we show that tumours histologically diagnosed as anaplastic ganglioglioma comprise a wide spectrum of CNS WHO tumour types with different prognostic and therapeutic implications. We therefore suggest assigning this designation with caution and recommend comprehensive molecular workup.

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“…In addition, DNA methylation profiling readily separated the class of PTPN11 -altered GG from PXA (Figure 2). Several publications describe composite tumors of variable entities, most often including GG and PXA (Lucas et al, 2022, Wang et al, 2022), a feature in need of further and systematic exploration in the LEAT cohort.…”

Section: Discussionmentioning

confidence: 99%

“…2 ). Several publications describe the composite tumors of variable entities, most often including GG and PXA [22, 35], a feature in need of further and systematic exploration in the LEAT cohort.…”

Section: Discussionmentioning

confidence: 99%

Alterations inPTPN11and other RAS-/MAP-Kinase pathway genes define ganglioglioma with adverse clinical outcome and atypic histopathological features

Hoffmann

Coras

Kobow

et al. 2022

Preprint

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The PTPN11 gene was recently described as a novel lesional epilepsy gene by extensive exome-wide sequencing studies. However, germline mutations of PTPN11 and other RAS-/MAP-Kinase signaling pathway genes cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11 gene compared to GG with other common MAP-Kinase signaling pathway alterations. Seventy-two GG were submitted to whole exome sequencing and genotyping and 86 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. Clinical data were retrieved from hospital files including postsurgical disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in FGFR4, RHEB, NF1, KRAS as well as BRAFV600E alterations. Histopathology revealed an atypical and complex glio-neuronal phenotype with subpial tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11 alterations were free of disabling-seizures two years after surgery (38% Engel I). This was remarkably different from our series of GG with BRAFV600E mutations (85% Engel I). Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by PTPN11 and other Noonan syndrome-related alterations of the RAS-/MAP-Kinase signaling pathway. These findings need prospective validation in clinical practice as they argue for an adapted WHO grading system in developmental, glio-neuronal tumors associated with early-onset focal epilepsy. These findings also open avenues for targeted medical treatment.

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Targeted Next-Generation Sequencing Reveals Divergent Clonal Evolution in Components of Composite Pleomorphic Xanthoastrocytoma-Ganglioglioma

Cited by 6 publications

References 21 publications

Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes

Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes

Anaplastic ganglioglioma—A diagnosis comprising several distinct tumour types

Alterations inPTPN11and other RAS-/MAP-Kinase pathway genes define ganglioglioma with adverse clinical outcome and atypic histopathological features

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