The molecular mechanism unraveling why a particular type of pediatric
brain tumor (pBT) behaves so differently from child to child or genetic/epigenetic changes in the mitochondrial genome vary from
tumor to
tumor is not clearly understood. Despite the identification of
mitochondrial DNA (
mtDNA) mutations in different types of pBT, the contribution of
mitochondrial dysfunction-related genes or
proteins that are selectively up- or down-regulated in pBT of different types has not been comprehensively examined. In the present study, we combined a 2D DIGE approach with
protein identification using MALDI-TOF MS and LC-MS/MS, coupled with
mtDNA genomics to screen brain samples for discovering changes in
protein expression, and
mtDNA sequence variation and
mtDNA copy number in the disease states. Two-dimensional gel electrophoresis-based differential proteomic analysis of the
brain tumors showed that 116
proteins were found to be up- or down-regulated in
brain tumors. Some of the
proteins up-regulated in
tumors compared to controls were
dihydropyrimidinase-like 2;
glial fibrillary acidic protein isoform 2;
phosphoserine aminotransferase isoform 1;
Sirt2 histone deacetylase; and C10orf2
protein, mitochondrial DNA helicase.
Proteins down-regulated in
brain tumors compared to controls were
heat shock protein 90 kDa beta, BiP;
guanine nucleotide binding protein (
G protein), beta
polypeptide 2-like 1,
isoform CRA_d;
histone H2B.1;
neurofilament, light polypeptide 68 kDa;
Annexin I; and RAN. These differentially expressed
proteins may provide useful information for developing molecular markers of diagnostic or prognostic value. To investigate further the role of
mitochondrial dysfunction, we examined the effects of
mtDNA copy number, oxidative damage, and
mtDNA variants as independent or combined risk factors for the development of pBTs. Bayesian network and mechanistic hierarchical structure Markov Chain Monte Carlo (MCMC) modeling were used to analyze the relationship between these variables. The combined effects of G3196, 9952A, 10006G, 100398G, oxidative
mtDNA damages, and
mtDNA copy number increased the probability of developing
brain tumors in female children by 51 times more when compared to normal incidence of pediatric
brain tumors. Comparison of mechanistic structure models also supported the finding that female children who have the wild type allele G3196, variant allele 9952A, variant allele 10006G, variant allele10398A, and high
mtDNA copy number had increased probability of developing pediatric
brain tumors. Estimation of nuclear genes controlling mitochondrial biogenesis and development of brain,
cortical dysplasia, and the effect of the environment using MCMC method showed that these latent variables had a very significant contribution in the development of pediatric
brain tumors. Together, these results suggest that mitochondrial genome and
tumor proteome are important contributors to
brain tumor risk in children, and findings from this study may guide the prospects for targeting mitochondria for therapeutic treatment of childhood
brain tumor.