Tumor mutational burden and driver mutations: Characterizing the genomic landscape of pediatric brain tumors

Patel, Roshal R.; Ramkissoon, Shakti; Ross, Jeffrey S.; Weintraub, Lauren

doi:10.1002/pbc.28338

Cited by 27 publications

(38 citation statements)

References 53 publications

(148 reference statements)

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“…For Patient 2, the loss of 17p included the selection of a mutant version of TP53 . Mutations in TP53 gene or in other genes implicated in this pathway are among the most frequent tumorigenic pathways in several pediatric malignancies [ 31 , 32 , 33 , 34 ]. In RB1

retinoblastoma, amplification and high expression of TP53 negative regulators MDM4 and MDM2 and loss of the MDM2 inhibitor p14ARF have been proposed as alternative mechanisms of p53 inactivation of its tumor suppresor function as the genetic inactivation of TP53 itself were only reported anecdotally [ 2 , 5 , 35 , 36 , 37 , 38 , 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma

Zugbi

Ganiewich

Bhattacharyya

et al. 2020

Cancers

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An uncommon subgroup of unilateral retinoblastomas with highly aggressive histological features, lacking aberrations in RB1 gene with high-level amplification of MYCN (MCYNamplRB1+/+) has only been described as intra-ocular cases treated with initial enucleation. Here, we present a comprehensive clinical, genomic, and pharmacological analysis of two cases of MCYNamplRB1+/+ with orbital and cervical lymph node involvement, but no central nervous system spread, rapidly progressing to fatal disease due to chemoresistance. Both patients showed in common MYCN high amplification and chromosome 16q and 17p loss. A somatic mutation in TP53, in homozygosis by LOH, and high chromosomal instability leading to aneuploidy was identified in the primary ocular tumor and sites of dissemination of one patient. High-throughput pharmacological screening was performed in a primary cell line derived from the lymph node dissemination of one case. This cell line showed resistance to broad spectrum chemotherapy consistent with the patient’s poor response but sensitivity to the synergistic effects of panobinostat–bortezomib and carboplatin–panobinostat associations. From these cells we established a cell line derived xenograft model that closely recapitulated the tumor dissemination pattern of the patient and served to evaluate whether triple chemotherapy significantly prolonged survival of the animals. We report novel genomic alterations in two cases of metastatic MCYNamplRB1+/+ that may be associated with chemotherapy resistance and in vitro/in vivo models that serve as basis for tailoring therapy in these cases.

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Section: Discussionmentioning

confidence: 99%

Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma

Zugbi

Ganiewich

Bhattacharyya

et al. 2020

Cancers

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“…However, veliparib treated cells had not completely repaired the radiation-induced DNA damage by the end of the experiment, warranting further investigation on the lasting mutational burden in these cells. This may be of particular importance since pediatric brain tumors are known to have low mutational burden, partially contributing to the relative lack of success with some immunotherapies ( Wang et al, 2019 ; Patel et al, 2020 ). In further support of a potential therapeutic benefit that may be achieved by combining veliparib and radiation is the increased γH2AX foci in medulloblastoma cells following combination treatment compared to radiation alone.…”

Section: Discussionmentioning

confidence: 99%

Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

Buck

Dyer

Hii

et al. 2021

Front. Mol. Biosci.

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Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan–Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.

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“…Thus, additional strategies such as targeted therapies and immunotherapy are currently under investigation. However, pediatric medulloblastoma is considered a tumor entity with minimal mutational load [ 23 ] and, therefore, low immunogenicity. Here, we identified a new fusion transcript potentially defining a more immunogenic subgroup of medulloblastoma.…”

Section: Discussionmentioning

confidence: 99%

Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1

Paret

Lehmann

Bender

et al. 2021

Cancers

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Medulloblastoma is the most common malignant brain tumor in children. Immunotherapy is yet to demonstrate dramatic results in medulloblastoma, one reason being the low rate of mutations creating new antigens in this entity. In tumors with low mutational burden, gene fusions may represent a source of tumor-specific neoantigens. Here, we reviewed the landscape of fusions in medulloblastoma and analyzed their predicted immunogenicity. Furthermore, we described a new in-frame fusion protein identified by RNA-Seq. The fusion involved two genes on chromosome 2 coding for the enhancer of polycomb homolog 2 (EPC2) and GULP PTB domain containing engulfment adaptor 1 (GULP1) respectively. By qRT-PCR analysis, the fusion was detected in 3 out of 11 medulloblastoma samples, whereby 2 samples were from the same patients obtained at 2 different time points (initial diagnosis and relapse), but not in other pediatric brain tumor entities. Cloning of the full-length sequence indicated that the fusion protein contains the N-terminal enhancer of polycomb-like domain A (EPcA) of EPC2 and the coiled-coil domain of GULP1. In silico analyses predicted binding of the neoantigen-derived peptide to HLA-A*0201. A total of 50% of the fusions described in the literature were also predicted to produce an immunogenic peptide. The EPC2-GULP1 fusion peptide was able to induce a de novo T cell response characterized by interferon gamma release of CD8+ cytotoxic T cells in vitro. While the functional relevance of this fusion in medulloblastoma biology remains to be clarified, our data support an immunotherapeutic approach for pediatric medulloblastoma patients carrying the EPC2-GULP1 fusion and other immunogenic fusions.

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Tumor mutational burden and driver mutations: Characterizing the genomic landscape of pediatric brain tumors

Cited by 27 publications

References 53 publications

Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma

Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma

Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1

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