Goschzik T, et al. - Researchers investigated novel prognostic biomarkers for standard-risk, non-WNT/non-SHH medulloblastoma. They assigned non-WNT/non-SHH medulloblastoma patients, normally classified as standard-risk, into favorable-risk and high-risk categories by means of a whole chromosomal signature that was defined in this study. They recommended future biomarker-driven, risk-adapted clinical trials to consider patients with non-WNT/non-SHH tumors with their defined whole chromosomal aberration signature and patients with SHH-TP53^wild-type tumors, in addition to patients younger than 16 years with WNT tumors, for therapy de-escalation. More intensive therapies could be beneficial for the remaining subgroups of patients with high-risk medulloblastoma.

Methods

• Hyperfractionated radiotherapy was compared to standard radiotherapy in 338 patients aged 4–21 years with medulloblastoma recruited in the HIT-SIOP PNET 4 trial between January 1, 2001 and December 31, 2006 in 120 treatment institutions in seven European countries.
• Researchers performed this retrospective analysis to evaluate the remaining tumor samples from patients in the HIT-SIOP PNET 4 trial (n=136).
• The molecularly defined WNT and SHH subgroups were evaluated with respect to clinical behavior.
• For standard-risk patients with non-WNT/non-SHH disease, novel independent prognostic markers and models were determined.
• On account of the scarcity and low quality of available genomic material, a mass spectrometry-minimal methylation classifier assay (MS-MIMIC) and a molecular inversion probe array was used to evaluate methylation subgroup and to detect genome-wide copy number aberrations, respectively.
• For the validation of the identified prognostic biomarkers and models, they opted an independent, demographically matched cohort (n=70) of medulloblastoma patients with non-WNT/non-SHH standard-risk disease treated with conventional therapies (maximal surgical resection followed by adjuvant craniospinal irradiation [all patients] and chemotherapy [65 of 70 patients]), at UK Children's Cancer and Leukaemia Group and European Society for Paediatric Oncology (SIOPE) associated treatment centers between 1990 and 2014.
• They used Illumina 450k DNA methylation microarray to analyze these samples.

Results

• In 136 assessable tumor samples from the HIT-SIOP PNET 4 cohort, representing 40% of the 338 patients in the trial cohort, analysis of methylation subgroup, genome-wide copy number aberrations, and mutational features was carried out.
• There were 136 samples included in this cohort, of which, 28 (21%) were classified as WNT, 17 (13%) as SHH, and 91 (67%) as non-WNT/non-SHH (the analysis was performed by considering Group3 and Group4 medulloblastoma together due to their similar molecular and clinical features).
• In patients younger than 16 years, it was confirmed that WNT tumors carried favorable outcomes.
• In patients with TP53 mutation (TP53^mut) or chromosome 17p loss, the occurrence of all relapse events in SHH (four [24%] of 17) was noted.
• In patients with non-WNT/non-SHH medulloblastoma in the HIT-SIOP PNET 4 cohort, a novel whole chromosomal aberration signature related to increased ploidy and multiple non-random whole chromosomal aberrations was identified in 38 (42%) of the 91 samples.
• Favorable prognosis was predicted by biomarkers related to this whole chromosomal aberration signature (at least two of chromosome 7 gain, chromosome 8 loss, and chromosome 11 loss).
• Reclassification of patients with non-WNT/non-SHH medulloblastoma as having favorable-risk or high-risk disease could be done by these markers.
• The observed 5-year event-free survival was 100% and 68% (95% CI 57·5–82·7; p=0·00014) in the favorable-risk group and in the high-risk group, respectively, in patients in the HIT-SIOP PNET4 cohort with non-WNT/non-SHH medulloblastoma, with a median follow-up of 6·7 years (IQR 5·8–8·2).
• In the favorable-risk group and in the high-risk group in the validation cohort, with a median follow-up of 5·6 years (IQR 3·1–8·1), the observed 5-year event-free survival was 94·7% (95% CI 85·2–100) and 58·6% (95% CI 45·1–76·1), respectively (hazard ratio 9·41, 95% CI 1·25–70·57; p=0·029).
• Subgroup-specific risk models that were identified in this comprehensive molecular investigation enabled researchers to assign 69 (51%) of 134 accessible patients from the standard-risk medulloblastoma HIT-SIOP PNET 4 cohort to a favorable-risk group.