ArticlesRecurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis
Introduction
Medulloblastoma is the most common malignant brain tumour of childhood.1, 2 With multimodal therapy, consisting of surgery, craniospinal irradiation, and adjuvant chemotherapy, 5-year overall survival approaches 85% for average-risk disease and 70% for high-risk disease.3, 4, 5 However, recurrent medulloblastoma is a great challenge, because it is almost always fatal in previously irradiated patients despite a multitude of therapies including re-resection, re-irradiation, high-dose chemotherapy with autologous stem-cell support, and enrolment in clinical trials.6 Integrative genomic studies have shown that medulloblastoma consists of at least four subgroups (WNT, SHH, group 3, and group 4) that are clinically, transcriptionally, and genetically distinct.2, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 Of these four subgroups, patients with WNT subgroup tumours have an excellent prognosis whereas patients with group 3 tumours have the worst prognosis and more commonly present with disseminated disease at diagnosis.1, 2, 12 Although these integrative genomic studies have shown that there are significant differences in survival between the four subgroups, little is known with respect to subgroup-specific anatomical and temporal characteristics of recurrence.
In glioblastoma, molecular subgroup affiliation can change at recurrence, partly because of intratumoural heterogeneity based on geographical location.19, 20 Although medulloblastoma subgroups have been shown to arise from distinct cells of origin, the stability of subgroup affiliation at recurrence remains unknown.21, 22, 23 Moreover, the clinical behaviour of the individual subgroups at recurrence has yet to be established. As such, an understanding of subgroup-specific temporal and spatial details could help to develop treatment of recurrent medulloblastoma, because the next generation of subgroup-specific clinical trials will probably be based initially in the context of recurrent medulloblastoma.
We aimed to characterise the subgroup-specific clinical patterns of recurrence in medulloblastoma.
Section snippets
Patients
We assembled a discovery cohort (cohort 1) and, to account for unobserved variables and potential bias due to different subgrouping methods, two non-overlapping validation cohorts (cohorts 2 and 3). Cohort 1 consisted of all patients with medulloblastoma with either frozen or formalin-fixed paraffin-embedded (FFPE) material along with clinical variables and survival data, treated between 1994 and 2012, at the Hospital for Sick Children (Toronto, ON, Canada).
Cohort 2 consisted of samples from
Results
Cohort 1 consisted of 131 patients, of whom 30 had recurrent medulloblastoma. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients, all of whom had recurrent medulloblastoma. At first diagnosis, the WNT subgroup was rare, occurring in one (3%) of 30 patients in cohort 1, no patients in cohort 2, and two (2%) of 96 patients in cohort 3. Specimens from the remaining patients were distributed roughly equally between SHH, group 3, and group 4 in all cohorts (table 1). Of the 96 cases in
Discussion
Our results show that medulloblastoma does not change subgroup at recurrence. This finding was not dependent on location of recurrence, because subgroup affiliation remained stable in both local tumour bed samples and metastatic samples at recurrence. We also identified significant differences across subgroups with respect to the anatomical and temporal patterns of recurrence, specifically SHH tumours recur mostly in the local tumour bed and group 3 and group 4 tumours recur almost exclusively
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