Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma

Abstract

Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M—including H3.2K27M—mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships.

H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas

“…K27M-P, K27M-AP and K27M-APP tumor cells were injected into the striatum of NOD-SCID mice, and brains were collected 45–70 days after transplantation. Histopathological analysis revealed that K27M-P, K27M-AP and K27M-APP cells formed 100% diffuse tumors with extensive spreading through striatal, dorsolateral and dorsomedial cortical regions, similar to what is observed in pHGG (Figure 4A and 4B) (Buczkowicz et al, 2014; Louis et al, 2016; Nikbakht et al, 2016). …”

“…H3.3 K27M -tumors and IDH-mutant gliomas possess co-occurring mutations in the same genes (Fontebasso et al, 2014; Khuong-Quang et al, 2012; Nikbakht et al, 2016; Wu et al, 2014). These include alterations affecting the p53 pathway in ~87% of H3.3 K27M tumors (Fontebasso and Jabado, 2015; Fontebasso et al, 2014; Nikbakht et al, 2016) and loss-of-function mutations in ATRX , which occur with increasing frequency in older patients (Fontebasso et al, 2014; Khuong-Quang et al, 2012; Nikbakht et al, 2016).…”

“…These include alterations affecting the p53 pathway in ~87% of H3.3 K27M tumors (Fontebasso and Jabado, 2015; Fontebasso et al, 2014; Nikbakht et al, 2016) and loss-of-function mutations in ATRX , which occur with increasing frequency in older patients (Fontebasso et al, 2014; Khuong-Quang et al, 2012; Nikbakht et al, 2016). Moreover, amplifications and rare mutations of the platelet-derived growth factor receptor alpha gene ( PDGFRA ) often co-occur with H3.3 K27M and TP53 mutations, indicating a potential role of this receptor in tumorigenesis (Flavahan et al, 2016; Khuong-Quang et al, 2012; Korshunov et al, 2015; Paugh et al, 2013).…”

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

“…Such studies may also allow new insights into the processes generating diversity and reveal how constraints to tumor evolution may be exploited, leveraging an adaptive immune response, permitting proactive management of cancers. (Nikbakht et al, 2016); Neuroblastoma (Eleveld et al, 2015); low-grade gliomba/glioblastoma multiforme Kim et al, 2015;Wang et al, 2016); breast cancer (Yates et al, 2015); clear cell renal cell carcinoma (Gerlinger et al, 2014a); multiple myeloma (Bolli et al, 2014); lung adenocarcinomas (de Bruin et al, 2014;Zhang et al, 2014);…”

Development of a targeted sequencing approach to identify prognostic, predictive and diagnostic markers in paediatric solid tumours

“…The discrepancies of the variants above 10% could be explained by variation in neoplastic cell content between FF and FFPE and intra-tumour heterogeneity leading to subclonal alterations. Three of the samples with more striking differences were brain tumours which are well known as highly heterogeneous tumours [42,43].…”