LAUSR

Medulloblastoma (MB) comprises four main molecular MB subgroups (WNT, SHH, Group 3 and Group 4) with divergent biology, outcomes and subgroup-specific differences in relapses [1–6]. Metastatic recurrences are most common in Group 3 and 4 MB, where metastases from a single patient are genetically similar to each other, but highly divergent from the corresponding primary tumor [2–6]. Local recurrences in the tumor bed are more frequent in SHH-activated tumors but progression-associated molecular aberrations for this MB variant remain unclear [2, 6]. To assess a biological evolution of SHH MB, we analyzed molecular changes appearing during local regrowth of desmoplastic nodular MB (DNMB). Eleven pairs of primary and recurrent DNMB samples were analyzed with DNAand RNA-based methods. Tumor samples were obtained by resection from three infants, two children, and six adults older than 17 years (all at M0 stage; Suppl. Table). After primary resection, infants received chemotherapy alone, while children and adults were treated according to HIT protocols that included craniospinal radiotherapy as well. Event-free survival varied widely for these 11 patients, ranging from 8 to 192 months, with infants on average relapsing earlier than non-infants (11 months vs. 82 months for others); all 11 “secondary” samples were obtained via resection of the local DNMB recurrences. Histopathological evaluation revealed that eight DNMB pairs from children and adults had similar histology at primary diagnosis and at relapse. However, DNMB features completely disappeared in three infant recurrent samples which were represented by poorly differentiated, reticulin-rich areas (Fig. 1a, b). Methylation profiling disclosed matched DNA profiles for all DNMB pairs which all were identified as “SHH MB” according to “Classifier v11b4” [1] thus excluding secondary non-MB malignancies (Suppl. Figure 1). Cytogenetic profiles of eight children and adult DNMB revealed no detectable differences between primary and recurrent tumors (Table 1). In stark contrast, all three infant DNMB initially disclosed flat genomes, but their recurrences showed various CNVs including 17p loss in all three cases (Table 1, Fig. 1d). Next-generation panel sequencing (depth X900) revealed either PTCH1 (8) or SMO (3) mutations; all three infants had both somatic and germ-line PTCH1 alterations despite of balanced 9q (Table 1). TERT promoter mutations were identified in 4/6 adult DNMB. Mutational profiles were similar in eight pairs Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s0040 1-019-02022 -y) contains supplementary material, which is available to authorized users.