Reference set (classifier version: 1.0)

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.
Name Description Details
Medulloblastoma, subclass group 3/4, subtype I The methylation class "medulloblastoma, subclass group 3/4, subtype I" is comprised of tumors with the diagnosis medulloblastoma. Histologically, most (85%) cases fall into the classic medulloblastoma group. Median age is 6 years (range 3 to 46). One third are M+. Male:Female ratio is 1.5:1. Subtype I medulloblastomas have no specific accumulation of recurrent cytogenetic changes, but are enriched for OTX2 amplification. Subtype I is a standard-risk group (5-year OS ~ 75% in retrospective series). This subtype is comprised of 25% Grp3 and 75% Grp4 subgroup tumors. show
Medulloblastoma, subclass group 3/4, subtype II The methylation class "medulloblastoma, subclass group 3/4, subtype II" is comprised of tumors with the diagnosis medulloblastoma. Histologically, most cases fall into the classic (50%) or large-cell/anaplastic group (45%) and 5% cases fall in the DN/MBEN group. Median age is 5 years (range 1 to 17). The majority (55%) are M+. Male:Female ratio is 3.3:1. Subtype II medulloblastomas are enriched for chr8 and chr17, isochromosome 17q (i17q) , chr13q gain and chr 16 loss, and are enriched for MYC amplification (20% of cases). Subtype% in II is high-risk (5-year OS ~ 49% in retrospective series). This subtype is comprised of 100% Grp3 subgroup tumors. show
Medulloblastoma, subclass group 3/4, subtype III The methylation class "medulloblastoma, subclass group 3/4, subtype III" is comprised of tumors with the diagnosis medulloblastoma. Histologically, most cases fall into the classic (80%) or large-cell/anaplastic group (20%). Median age is 5 years (range 2 to 50). The majority (55%) are M+. Male:Female ratio is 3.6:1. Subtype III medulloblastomas are enriched for a characteristic 1q gain, and are enriched for MYC amplification (10% of cases). Subtype% in III is high-risk (5-year OS ~ 41 in retrospective series). This subtype is comprised of 100% Grp3 tumors. show
Medulloblastoma, subclass group 3/4, subtype IV The methylation class "medulloblastoma, subclass group 3/4, subtype IV" is comprised of tumors with the diagnosis medulloblastoma. Histologically, most cases (85%) fall into the classic group. Median age is 3 years (range 0.5 to 14). The majority (55%) are M+. Male:Female ratio is 2.1:1. Subtype IV medulloblastomas are enriched for 5q gain and 14q gain. Subtype% in IV is standard-risk (5-year OS ~ 80 in retrospective series.). This subtype is comprised of 100% Grp3 tumors. show
Medulloblastoma, subclass group 3/4, subtype V The methylation class "medulloblastoma, subclass group 3/4, subtype V" is comprised of tumors with the diagnosis medulloblastoma. Histologically, most cases (80%) fall into the classic group. Median age is 8 years (range 2.5 to 17). The majority (60%) are M+. Male:Female ratio is 2.4:1. Subtype V medulloblastomas are enriched for a 17p loss and i17q, and are enriched for MYC amplification (12% of cases) or MYCN amplification (20% of cases). Subtype% in V is high-risk (5-year OS ~ 58 in retrospective series). This subtype is comprised of 85 % Grp4 tumors and 15 % Grp3 tumors. show
Medulloblastoma, subclass group 3/4, subtype VI The methylation class "medulloblastoma, subclass group 3/4, subtype VI" is comprised of tumors with the diagnosis medulloblastoma. Histologically, most cases (75%) fall into the classic group. Median age is 7 years (range 2.5 to 19). 45% of tumors are M+. Male:Female ratio is 2.0:1. Subtype VI medulloblastomas are enriched for chr7 aberrations along with 17p loss and i17q. Subtype% in VI is standard-risk (5-year OS ~ 80 in retrospective series). This subtype is comprised of 99% Grp4 tumors and, rarely, Grp3 tumors. show
Medulloblastoma, subclass group 3/4, subtype VII The methylation class "medulloblastoma, subclass group 3/4, subtype VII" is comprised of tumors with the diagnosis medulloblastoma. Histologically, most cases (85%) fall into the classic group. Median age is 7.5 years (range 0.5 to 28). 45% of tumors are M+. Male:Female ratio is 2.0:1. Subtype VII medulloblastomas are enriched for 10q loss, and are not typically MYC or MYCN amplified like some of the other subtypes. Subtype% in VII is standard-risk (5-year OS ~ 83 in retrospective series). This subtype comprises of 90% Grp4 tumors and 10% Grp3 tumors. show
Medulloblastoma, subclass group 3/4, subtype VIII The methylation class "medulloblastoma, subclass group 3/4, subtype VIII" is comprised of tumors with the diagnosis medulloblastoma. Histologically, the majority of cases (95%) fall into the classic group. Median age is 10 years (range 3.0 to 48). 49% of tumors are M+. Male:Female ratio is 3.0:1. Subtype VIII medulloblastomas are not typically MYC or MYCN amplified. Subtype% in VIII is high-risk (5-year OS ~ 35 in retrospective series) , and is notable for its association with late relapse 5 years and longer after primary diagnosis. This subtype is comprised of 100% Grp4 tumors. show