Abstract 3583: Computational analysis of mutations on neural signaling factors existing in childhood cancer

Abstract

Abstract The role of the nervous system in adult tumor progression has been hypothesized. In contrast, the involvement of nervous system in childhood cancer is still unknown but it results of particular interest. The main objective of this study is to identify whether mutations in neuron signaling proteins are present in pediatric cancer. Additionally this study foresees to determine the effect of mutation on the protein structure and function and to elucidate if differences between solid and hematopoietic pediatric tumors exist in terms of neural signaling. The genomic data of pediatric cancers available in the Pediatric Cancer Data Portal (PeCan) were mined looking for point mutations in the genes of interest. The analysis comprised a set of well recognized neuron signaling factors including 50 neurotrophic growth factors, 23 axon guidance molecules and 47 neurotransmitter receptors. Missense mutations were retrieved per gene and tumor type. The effect of each mutation on the protein function was predicted through BioMuta, a well curated and annotated database. Our results showed the existence of genetic mutations in neuron signals across 16 childhood tumor types. Neuroblastoma (NBL) was the most mutated solid tumor with a total of 26 mutated genes out of 120 study genes. B-cell Acute Lymphoblastic Leukemia (BALL) was the most frequently mutated hematopoietic malignancy resulting with 17 mutated genes out of 120 study genes. EGFR was the most mutated gene within the group of neurotrophic molecules, with 14 missense mutations across 6 different tumor types. A total of 8 out of 14 mutations reported in EGFR were classified as damaging mutated phenotype and these were present in NBL, glioma, BALL and Acute Myeloid Leukemia (AML). EPHA3, ROBO3, RBP1, and PLXNB1 were the most frequently mutated genes within the group of axon guidance molecules, with 3 missense mutations each one across 7 tumor types, most of them categorized as damaging mutations. GRIN2B was the most frequently mutated gene within the group of neurotransmitter receptors with 3 missense mutations including one damaging mutation found in NBL. A number of damaging mutations here identified corresponded to “Gain of function” mutations such as the T790M EGFR driver mutant present in pediatric AML. The genetic mutations here compiled on neurosignaling molecules may increase the response of tumor cells to neurotransmitters, axon guidance molecules and neurotrophic factors that ultimately may boost their growth and metastatic capacity. Our data show that neurotrophic factors as well as axon guidance molecules and neurotransmitter receptors are structurally and functionally altered in childhood cancer patients, both in hematopoietic and solid tumors. The influence of nervous system in the tumorigenesis and cancer progression may have a relevant role thus raising important implications for future therapies for childhood cancer. Citation Format: Claudia Machicado. Computational analysis of mutations on neural signaling factors existing in childhood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3583. doi:10.1158/1538-7445.AM2017-3583