Elucidating the molecular pathogenesis of glioma: integrated germline and somatic profiling of a familial glioma case series

Jacobs, Daniel; Fukumura, Kazutaka; Bainbridge, Matthew N.; Armstrong, Georgina; Tsavachidis, Spiridon; Gu, Xiangjun; Doddapaneni, Harshavardhan; Hu, Jianhong; Jayaseelan, Joy C.; Huse, Jason T.; Bondy, Melissa L.

doi:10.1093/neuonc/noy119

Cited by 14 publications

(17 citation statements)

References 43 publications

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“…The observation that glioblastoma and anaplastic astrocytoma, and to a lesser extent colorectal cancers, were less likely to harbour POT1 mutations than other tumour types suggests that when these tumours arise in the context of germline POT1 deficiency, they are using non-canonical pathways of telomere maintenance. This is underscored by our observation that POT1 -mutated tumours had higher TMB, fewer ATRX mutations, and our previous report that glioma patients with germline POT1 mutations lacked a hallmark telomere-maintenance mutation in either ATRX or the TERT promoter 31. Our results provide insight into the various roles that POT1 may play across a diverse group of tumours.…”

Section: Discussionsupporting

confidence: 64%

“…The frequency of POT1 mutations was lower in glioma, particularly high-grade malignant glioblastoma, relative to other tumour types, indicating that POT1 mutations are likely not a major contributor to gliomagenesis in non-familial cases. In our previous observations of 20 familial glioma patients, those harbouring a germline mutation in the shelterin complex genes POT1 or TERF2 were the only patients not to have a somatic TERT promoter or ATRX mutation 31. As the vast majority of gliomas maintain telomere length by reactivating TERT expression through hotspot TERT promoter mutations34 or by activating ALT through loss of ATRX ,35 it is possible that, in rare instances, POT1 mutations activate a non-canonical mechanism of ALT via shelterin dysfunction.…”

Section: Discussionmentioning

confidence: 86%

“…This indicates that shelterin complex dysfunction may be a key contributor to angiosarcoma development. Pathogenic mutations were detected in both the oligonucleotide/oligosarccharide and the TPP1-binding domains of POT1 , previously associated with abnormally long telomeres and telomere fragility,10 15 28 29 genomic instability and tumourigenesis 4 30–32. Further studies are required to reveal which of the reported POT1 mutations are particularly damaging and which POT1-dependent molecular mechanisms are critically involved.…”

Section: Discussionmentioning

confidence: 99%

“…We previously identified three germline POT1 variants in association with familial glioma 12. While all affected individuals in these families were found to have oligodendroglioma or mixed oligoastrocytoma, a subsequent molecular analysis revealed that at least one proband had a molecular astrocytoma according to revised 2016 WHO criteria (ie, Isocitrate Dehydrogenase 1 -mutated, 1 p/19q intact) 31. Here we have identified POT1 mutations in the tumour genome of astrocytic-lineage gliomas (eg, glioblastoma and anaplastic astrocytoma) but not oligodendroglioma.…”

Section: Discussionmentioning

confidence: 99%

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POT1 mutation spectrum in tumour types commonly diagnosed among POT1-associated hereditary cancer syndrome families

et al. 2020

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BackgroundThe shelterin complex is composed of six proteins that protect and regulate telomere length, including protection of telomeres 1 (POT1). Germline POT1 mutations are associated with an autosomal dominant familial cancer syndrome presenting with diverse malignancies, including glioma, angiosarcoma, colorectal cancer and melanoma. Although somatic POT1 mutations promote telomere elongation and genome instability in chronic lymphocytic leukaemia, the contribution of POT1 mutations to development of other sporadic cancers is largely unexplored.MethodsWe performed logistic regression, adjusted for tumour mutational burden, to identify associations between POT1 mutation frequency and tumour type in 62 368 tumours undergoing next-generation sequencing.ResultsA total of 1834 tumours harboured a non-benign mutation of POT1 (2.94%), of which 128 harboured a mutation previously reported to confer familial cancer risk in the setting of germline POT1 deficiency. Angiosarcoma was 11 times more likely than other tumours to harbour a POT1 mutation (p=1.4×10−20), and 65% of POT1-mutated angiosarcoma had >1 mutations in POT1. Malignant gliomas were 1.7 times less likely to harbour a POT1 mutation (p=1.2×10−3) than other tumour types. Colorectal cancer was 1.2 times less likely to harbour a POT1 mutation (p=0.012), while melanoma showed no differences in POT1 mutation frequency versus other tumours (p=0.67).ConclusionsThese results confirm a role for shelterin dysfunction in angiosarcoma development but suggest that gliomas arising in the context of germline POT1 deficiency activate a telomere-lengthening mechanism that is uncommon in gliomagenesis.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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POT1 mutation spectrum in tumour types commonly diagnosed among POT1-associated hereditary cancer syndrome families

et al. 2020

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“…For example, two POT1 germline mutations (p.Gly95Cys and p.Glu450*) were identified among one cohort of familial glioma cases (3.6%, n = 2/55), and an additional germline variant (p.Asp617Glufs) was discovered in another cohort (0.4%, n = 1/246) [ 96 ]. In a subsequent study, the germline and somatic molecular profiles of cancer samples were generated from 20 unrelated familial glioma patients, and these same POT1 inherited variants were identified in two cases (10%, n = 2/20), in addition to an acquired POT1 mutation at p.Arg117His (5%, n = 1/20) [ 97 ].…”

Section: Germline and Somatic Pot1 Mutations Inmentioning

confidence: 99%

Role of POT1 in Human Cancer

Poulos

Reddel

2020

Cancers

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Telomere abnormalities facilitate cancer development by contributing to genomic instability and cellular immortalization. The Protection of Telomeres 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex. It directly binds to single-stranded telomeric DNA, protecting chromosomal ends from an inappropriate DNA damage response, and plays a role in telomere length regulation. Alterations of POT1 have been detected in a range of cancers. Here, we review the biological functions of POT1, the prevalence of POT1 germline and somatic mutations across cancer predisposition syndromes and tumor types, and the dysregulation of POT1 expression in cancers. We propose a framework for understanding how POT1 abnormalities may contribute to oncogenesis in different cell types. Finally, we summarize the clinical implications of POT1 alterations in the germline and in cancer, and possible approaches for the development of targeted cancer therapies.

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Downregulation of CYP2E1 is associated with poor prognosis and tumor progression of gliomas

Wang

et al. 2021

Cancer Medicine

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Objective To explore the role and possible regulatory mechanisms of CYP2E1 in gliomas. Methods RNA‑seq data and corresponding clinical information of glioma patients were collected from The Cancer Genome Atlas and Chinese Glioma Genome Atlas, and mRNA data of normal brain tissues were obtained by the Genotype‐Tissue Expression project. The Wilcoxon test was performed to analyze the correlation between CYP2E1 expression and glioma subtypes. Univariate and multivariate Cox proportional hazards regression, receiver operating characteristic curves, and Kaplan–Meier plots were used to evaluate the prognostic value of CYP2E1 in glioma. Functional enrichment analyses and immune infiltration analyses were performed to investigate the potential function of CYP2E1 in gliomas. Moreover, we investigated the miRNA and epigenetic mechanisms that regulate CYP2E1 expression. Finally, network pharmacology and molecular docking experiments were used to predict drugs that target CYP2E1. Results The downregulation of CYP2E1 expression may predict a poor prognosis for glioma patients. CYP2E1 expression decreased with increasing WHO grade (II–IV), and its level was correlated with clinical features, including age, 1p19q codeletion status, and IDH state in glioma tissues. Furthermore, CYP2E1 was involved in lipid metabolism and ferroptosis and related to the tumor immune microenvironment due to its strong correlation with the levels of infiltrating monocytes and Tregs. Moreover, variation in the total methylation level and copy number of CYP2E1 was moderately correlated with its mRNA expression (p < 0.05). CYP2E1 was predicted to be targeted by hsa‐miR‐527, whose expression was negatively related to CYP2E1 mRNA expression (p < 0.05). In addition, effective compounds that target CYP2E1, including 18beta‐glycyrrhetinic acid, styrene, toluene, nicotine, m‐xylene, p‐xylene, and colchicine, were identified. Conclusion The downregulation of CYP2E1, which affects lipid metabolism and the ferroptosis signaling pathway, promotes the progression of gliomas.

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Elucidating the molecular pathogenesis of glioma: integrated germline and somatic profiling of a familial glioma case series

Abstract: 1. Familial and sporadic gliomas display highly comparable molecular landscapes. 2. Germline and somatic molecular events target common core pathways involved in gliomagenesis. 3. Carriage of germline glioma risk variants is not associated with somatic events in the same gene.

Cited by 14 publications

References 43 publications

POT1 mutation spectrum in tumour types commonly diagnosed among POT1-associated hereditary cancer syndrome families

POT1 mutation spectrum in tumour types commonly diagnosed among POT1-associated hereditary cancer syndrome families

Role of POT1 in Human Cancer

Downregulation of CYP2E1 is associated with poor prognosis and tumor progression of gliomas

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