Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma

Abstract

PURPOSE We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse

“…Downloaded from https://academic.oup.com/neuro-oncology/advance-article/doi/10.1093/neuonc/noab178/6323243 by University of Northumbria user on 04 October 2021 characteristics. This is in contrast to findings by Kumar et al, which similarly reported subtype divergence in 15/69 rMB (subtypes III, V, VI, VII, VIII at diagnosis), and proffered an association with MYC amplification or chromosome 2p gain at relapse 11. However, such cases were infrequent in both studies, and the nature, biological and clinical significance of these rare subtype switchers requires further investigation.…”

“…[7][8][9][10] Most recently, Kumar et al showed that the degree and patterns of molecular conservation at relapse vary according to disease subgroup. 11 Mutations of TP53 have been commonly identified in rMB, and can be both selectively maintained from diagnosis,…”

mTORC1 promotes malignant large cell/anaplastic histology and is a targetable vulnerability in SHH-TP53 mutant medulloblastoma

“…To increase the applicability of this therapeutic paradigm, we may take into consideration the fact that patients with recurrent MB often present with LC/A histology and with TP53 mutations that were undetected in the primary tumor ( 46 ). In fact, loss of function of Trp53 is identified as a key event in the pathogenesis of recurrence ( 38 , 46 – 48 ). Specifically, genetic events in TP53 pathway genes or in the actual TP53 gene are frequent in recurrences, predominantly in SHH MB ( 38 , 48 ).…”

“…In fact, loss of function of Trp53 is identified as a key event in the pathogenesis of recurrence ( 38 , 46 – 48 ). Specifically, genetic events in TP53 pathway genes or in the actual TP53 gene are frequent in recurrences, predominantly in SHH MB ( 38 , 48 ). Very interestingly, the mouse model used for modeling posttreatment MB recurrence, namely a Tp53 mut transposon-driven MB model, shows large cells, nuclear atypia, and nuclear molding that are all typical features of LC/A histology ( 49 ).…”

MYCN in Neuroblastoma: “Old Wine into New Wineskins”

“…On the other hand, MYCN has received less attention with respect to pediatric brain tumors, while recent reports have highlighted its role in the disease [ 9 , 10 , 11 ]. Apart from its role in neuroblastoma, MYCN has been studied in some extent for other pediatric brain neoplasms such as medulloblastoma [ 12 , 13 ], astrocytoma [ 14 ], glioblastoma [ 15 , 16 ], and others. One of the main questions in MYCN biology is the link between its overexpression and amplification.…”