Circumscribed/non-diffuse histology confers a better prognosis in H3K27M-mutant gliomas

Pratt, Drew; Natarajan, Siva Kumar; Banda, Adam; Giannini, Caterina; Vats, Pankaj; Koschmann, Carl; Mody, Rajen; Chinnaiyan, Arul M.

doi:10.1007/s00401-018-1805-3

Cited by 56 publications

(43 citation statements)

References 6 publications

(4 reference statements)

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“…This represents an important diagnostic achievement due to the relative efficiency and cost effectiveness of IHC staining compared to molecular sequencing analysis. In addition, diffuse midline glioma tissue is typically obtained via stereotactic tumor biopsy, limiting the amount specimen available for molecular analysis [14, 15]. While detection of H3K27M mutant and associated reduction of H3K27me3 is reported [16], H3K27Ac co-enrichment in H3K27M mutant tumors was not previously explored.…”

Section: Introductionmentioning

confidence: 99%

Detection of histone H3 K27M mutation and post-translational modifications in pediatric diffuse midline glioma via tissue immunohistochemistry informs diagnosis and clinical outcomes

Huang

García

et al. 2018

Oncotarget

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Pediatric diffuse midline glioma is a highly morbid glial neoplasm that may arise in the thalamus or brainstem (also known as diffuse intrinsic pontine glioma or DIPG). Because tumor anatomic location precludes surgical resection, diagnosis and treatment is based on MR imaging and analysis of biopsy specimens. Up to 80% of pediatric diffuse midline gliomas harbor a histone H3 mutation resulting in the replacement of lysine 27 with methionine (K27M) in genes encoding histone H3 variant H3.3 (H3F3A) or H3.1 (HIST1H3B). H3K27M mutant glioma responds more poorly to treatment and is associated with worse clinical outcome than wild-type tumors, so mutation detection is now diagnostic for a new clinical entity, diffuse midline glioma H3K27M mutant, as defined in the most recent WHO classification system. We previously reported patterns of histone H3 trimethylation (H3K27me3) and acetylation (H3K27Ac) associated with H3K27M mutation that impact transcription regulation and contribute to tumorigenesis. Given the clinical implications of the H3K27M mutation and these associated H3 post-translational modifications (PTMs), we set to determine whether they can be characterized via immunohistochemistry (IHC) in a cohort of pediatric glioma (n = 69) and normal brain tissue (n = 4) specimens. We observed 100% concordance between tissue IHC and molecular sequencing for detecting H3K27M mutation. In turn, H3K37M and H3K27me3 results, but not H3K27Ac staining patterns, were predictive of clinical outcomes. Our results demonstrate H3K27M and H3K27me3 staining of pediatric glioma tissue may be useful for diagnosis, stratification to epigenetic targeted therapies, and longitudinal monitoring of treatment response.

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Section: Introductionmentioning

confidence: 99%

Detection of histone H3 K27M mutation and post-translational modifications in pediatric diffuse midline glioma via tissue immunohistochemistry informs diagnosis and clinical outcomes

Huang

García

et al. 2018

Oncotarget

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“…However, recent studies have identified these mutations in other histologic subtypes, where the outcome may be relatively more favorable (29, 40). These include circumscribed gliomas, that may also have other known drivers including BRAF p.V600E or NF1 mutations (34). Additionally, recent studies suggest that H3-K27M may develop subclonally, presumably during tumor progression rather than an initiating event (24).…”

Section: Discussionmentioning

confidence: 99%

Alternative lengthening of telomeres, ATRX loss and H3‐K27M mutations in histologically defined pilocytic astrocytoma with anaplasia

et al. 2018

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Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fifty-seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3-75) were included. A clinical diagnosis of NF1 was present in 8 (22%). Alternative lengthening of telomeres (ALT) was assessed by telomere-specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF, ATRX, CDKN2A/p16, mutant IDH1 p.R132H and H3-K27M proteins. ALT was present in 25 (69%) cases and ATRX loss in 20 (57%), mostly in the expected association of ALT+/ATRX- (20/24, 83%) or ALT-/ATRX+ (11/11, 100%). BRAF duplication was present in 8 (of 26) (31%). H3-K27M was present in 5 of 32 (16%) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PA-A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3-K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas.

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“…In the retrospective analysis of 289 pediatric low‐grade glioma by Yang et al, 23 they constituted 6% and were allocated to a “high‐risk group”. Co‐occurrence with other genetic alterations was described for various low grade histologies, 10,41 but was not seen in our tumors that were uniformly progressive within few months and all patients died. We advocate to test all diffuse midline gliomas for this mutation to identify and exclude Histone3‐K27M ‐mutated midline diffuse gliomas in future pediatric LGG protocols, even if they lack signs of anaplasia.…”

Section: Discussionmentioning

confidence: 49%

“…The most striking finding was the presence of Histone3‐K27M ‐mutation in four midline tumors (6%). Histone3 ‐mutations are a hallmark of malignant diffuse midline glioma WHO‐grade IV according to the WHO‐classification, 1 but have also been described in low‐grade circumscribed 41 and diffuse, mostly thalamic and brainstem tumors 23,42 preceding malignant evolution 43 and death 6,23,41 . In the retrospective analysis of 289 pediatric low‐grade glioma by Yang et al, 23 they constituted 6% and were allocated to a “high‐risk group”.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO‐grade II—Report from the German/Swiss SIOP‐LGG 2004 cohort

Falkenstein

Gessi

Kandels

et al. 2020

Intl Journal of Cancer

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Reports on pediatric low‐grade diffuse glioma WHO‐grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2‐entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub‐entities proved unfavorable for survival. Within the prospectively registered, population‐based German/Swiss SIOP‐LGG 2004 cohort 100 patients (age 0.8‐17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event‐free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3‐K27M‐mutation in 4, IDH1‐mutation in 11, BRAF‐V600‐mutation in 12, KIAA1549‐BRAF‐fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549‐BRAF‐fusions. Histone3‐K27M‐mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2‐entities, with the exemption of Histone3‐K27M‐mutant tumors that require a HGG‐related treatment strategy. Our data confirm the importance to genetically define pediatric low‐grade diffuse gliomas for proper treatment decisions and risk assessment.

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Circumscribed/non-diffuse histology confers a better prognosis in H3K27M-mutant gliomas

Cited by 56 publications

References 6 publications

Detection of histone H3 K27M mutation and post-translational modifications in pediatric diffuse midline glioma via tissue immunohistochemistry informs diagnosis and clinical outcomes

Detection of histone H3 K27M mutation and post-translational modifications in pediatric diffuse midline glioma via tissue immunohistochemistry informs diagnosis and clinical outcomes

Alternative lengthening of telomeres, ATRX loss and H3‐K27M mutations in histologically defined pilocytic astrocytoma with anaplasia

Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO‐grade II—Report from the German/Swiss SIOP‐LGG 2004 cohort

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