Reference set (classifier version: 2.0)
The reference set is highly reminiscent of the WHO classification of brain tumors but not identical. For the constriction of the reference set at least 8 typical cases of each histological subtype described in the WHO classification of brain tumors were collected and underwent critical histological review. If available, only cases at first diagnosis and prior to radiation or chemotherapy were selected. For the majority of cases DNA was extracted from formalin fixed paraffin embedded tumor tissue. A special focus was set on tumor purity with rigorous dissection of areas with maximal tumor cell content.
The cases were then defined as a group for the random forest algorithm (supervised learning algorithm) and tested by cross validation. For cases with repeated misclassification unsupervized clustering was performed with the aim to identify to the DNA methylation core group within the histological group. This led to the splitting of various WHO entities (e.g. PNET with 4 molecular subtypes, subependymoma splitting into supratentorial, posterior fossa and spinal subtype). For other rare WHO entities we were either so far not able to obtain enough cases to incorporate the group into the classifier or there was no indication of a group by unsupervized clustering (e.g. astroblastoma). This is why our reference set strongly resembles the WHO classification but is not identical.
|Methylation class family meningiomas intermediate||Methylation class family meningiomas intermediate||show|
|Methylation class malignant||Meningiomas of methylation class malignant show usually highly perturbed copy number profiles, including deletions of 22q, 1p, 10, 14, and CDKN2A/B. However, focal deletions of BAP1 with otherwise flat copy-number profiles have also been observed. Most cases have NF2 mutations, some in addition mutations of the TERT promoter. The risk of recurrence is higher than for the average of cases histologically diagnosed as grade III meningioma, in one study with approximately 75% recurrence rate at 24 months.||show|
|Methylation class meningiomas benign-1||Meningiomas of methylation class benign-1 usually harbour deletions of 22q and NF2 mutations. Other chromosomal aberrations or mutations are rare. Histology mostly resembles the fibroblastic or transitional subtype. Risk of recurrence after complete resection is low.||show|
|Methylation class meningiomas benign-2||Meningiomas of methylation class benign-2 have usually flat copy-number-profiles and are enriched for cases with TRAF7 mutations in combination with mutations of AKT1 or KLF4, and for SMO mutations. Cases with meningothelial (particularly enriched for AKT1/TRAF7 mutations) or secretory (KLF4 mutation) histology mostly fall into this methylation class. Risk of recurrence after complete resection is low. If present, AKT1E17K mutations offer a target for treatment in cases in which complete resection is not feasible.||show|
|Methylation class meningiomas benign-3||Meningiomas of methylation class benign-3 often show chromosomal gains, particularly including chromosome 5. About half of these cases also have 22q deletions and NF2 mutations. The histological variants of metaplastic, microcytic, and angiomatous meningioma are enriched in this methylation class. Risk of recurrence after complete resection is low.||show|
|Methylation class meningiomas intermediate-A||Meningiomas of methylation classes intermediate A/B have frequently deletion of 22q and mutations of NF2, but in addition often deletions of 1p, 10, and 14. A subset can also present with CDKN2A/B deletion. TERT promoter mutations can occur but are rare in this methylation class. A large share shows increased mitotic count, but some cases may by histologically inconspicuous. In one study, risk of recurrence was about 50% within 48 months.||show|
|Methylation class meningiomas intermediate-B||Meningiomas of methylation classes intermediate A/B have frequently deletion of 22q and mutations of NF2, but in addition often deletions of 1p, 10, and 14. A subset can also present with CDKN2A/B deletion. TERT promoter mutations can occur but are rare in this methylation class. A large share shows increased mitotic count, but some cases may by histologically inconspicuous. In one study, risk of recurrence was about 50% within 48 months.||show|