Genomic Insights into Diffuse Intrinsic Pontine Glioma

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor with a peak incidence in middle childhood and a median survival of less than 1 year. The dismal prognosis associated with DIPG has been exacerbated by the failure of over 250 clinical trials to meaningfully improve survival compared with radiotherapy, the current standard of care. The traditional practice to not biopsy DIPG led to a scarcity in available tissue samples for laboratory analysis that till recently hindered therapeutic advances. Over the past few years, the acquisition of patient derived tumor samples through biopsy and autopsy protocols has led to distinct breakthroughs in the identification of key oncogenic drivers implicated in DIPG development. Aberrations have been discovered in critical genetic drivers including histone H3, ACVR1, TP53, PDGFRA, and Myc. Mutations, previously not identified in other malignancies, highlight DIPG as a distinct biological entity. Identification of novel markers has already greatly influenced the direction of preclinical investigations and offers the exciting possibility of establishing biologically targeted therapies. This review will outline the current knowledge of the genomic landscape related to DIPG, overview preclinical investigations, and reflect how biological advances have influenced the focus of clinical trials toward targeted therapies.

Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant

“…We identified that approximately 80% of tumors had H3F3A or HIST1H3B mutation. This rate is consistent with previous studies (25). No HIST1H3C mutation was found, likely reflecting its rarity (27).…”

“…The median overall survival of patients with H3K27M-mutant tumors was 7.95 months, which is in line with previous studies (23). As expected, within histone mutant tumors, p53 pathway alteration was the most frequent finding (65.71%), followed by PIK3CA/PIK3R1 mutations (14.29%) (25,29). ACVR1 mutations were identified in 11.76% of H3K27Mmutant tumors.…”

“…Brain tumors are the second most frequent malignancies in children and adolescents (18,36). Within this heterogeneous group of tumors, diffuse midline gliomas-including diffuse intrinsic pontine gliomas (DIPG)-are highly aggressive, with a median survival ranging from 9 to 12 months (25). Due to their location, complete surgical removal is impossible.…”

“…These mutations are found in diffuse midline gliomas, account for up to 84% of DIPG cases and are associated with worse outcomes (7). Other molecular alterations were next described, affecting genes such as ACVR1, TP53, PDGFRA, PIK3CA and MYC (25).…”

Diffuse Intrinsic Pontine Glioma: Translation of Genomic Knowledge to Clinical Practice

“…

Pediatric brain tumors account for approximately 25% of all cancers in children and are currently the leading cause of cancer-related deaths in the pediatric population with an estimated incidence of 5.14 cases per 100,000 person years [1]. Up to 10-15% of all pediatric brain tumors arise in the brainstem, with the majority of these classified as the diffuse intrinsic pontine glioma (DIPG) subtype [2].

…”