Neuroblastoma, the most common extracranial solid tumor of childhood, can present in multiple primary sites, but the extent of genetic heterogeneity among tumor foci, as well as the presence or absence of common oncogenic drivers, remains unknown. Although PHOX2B genetic aberrations can cause familial neuroblastoma, they demonstrate incomplete penetrance with respect to neuroblastoma pathogenesis, suggesting that additional undescribed oncogenic drivers are necessary for tumor development. We performed comprehensive molecular characterization of neuroblastoma tumors from two siblings affected by familial multifocal neuroblastoma, including whole exome sequencing and single‐nucleotide polymorphism (SNP) arrays of tumor and matched blood samples. Data were processed and analyzed using established bioinformatics algorithms to evaluate for germline and somatic mutations and copy number variations (CNVs). We confirmed the presence of a PHOX2B deletion and NF1 mutation across all tumor samples and the germline genome. Matched tumor‐blood whole exome sequencing also identified 365 genes that contained nonsilent coding mutations across all tumor samples, with no recurrent mutations across all tumors. SNP arrays also showed significant heterogeneity with respect to CNVs. The only common CNV across all tumors was 17q gain, with differing chromosomal coordinates across samples but a common region of overlap distal to 17q21.31, suggesting this adverse prognostic biomarker may offer insight about additional drivers for multifocal neuroblastoma in patients with germline PHOX2B or NF1 aberrations. Molecular characterization of all tumors from patients with multifocal primary neuroblastoma has potential to yield novel insights on neuroblastoma pathogenesis.
Emergence of therapy resistance greatly reduces long-term utility of effective targeted therapies, including SMO/SHH pathway inhibitors. SHH signaling is activated in ~25% of human medulloblastomas (MB) and FDA approved SMOi (to treat basal cell carcinoma (BCC)) are currently in clinical trials for MBs and acute myeloid leukemia (AML). Accumulating clinical experience suggests that a significant number of BCC patients treated with SMOi develop acquired resistance over time and some show de novo resistance. A similar pattern is observed in MB patients, indicating the need to elucidate resistance mechanisms, particularly those driving de novo vs. acquired resistance, and develop new strategies to overcome both de novo and acquired resistance to SMOi. We report that we have discovered a novel, epigenetic mechanism of therapy resistance to SMOi that underlie de novo resistance. Using two different mouse models of SHH MB, we tested our original hypothesis that the selective pressure on cancer stem cells (CSCs), but not bulk tumor cells, will determine the resistance mechanism at the molecular level. We show that acquired mutations in the SHH pathway genes (previously reported mechanism of resistance) occur only in tumors that contain CSCs that depend on the SHH pathway. In tumors where only the bulk tumor cells, but not CSCs, depend on SHH signaling, no acquired mutations in the SHH pathway genes are detected. Instead, in these tumors, epigenetic reprogramming through selective degradation of specific histone modifiers results in global changes in the epigenetic cell state and gene expression patterns. Importantly, we can predict the mechanism of resistance in individual tumors prior to treatment based on CSC phenotypes. Finally, we also report biomarkers that can be used to identify tumors with CSCs that are independent of SHH pathway, which can be exploited to design anticipatory combination therapies in the future.
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