RESUMEN
Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.
Asunto(s)
Neoplasias Encefálicas/genética , Reordenamiento Génico , Meduloblastoma/genética , Proteína p53 Supresora de Tumor/genética , Animales , Niño , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Humanos , Leucemia Mieloide Aguda/genética , Síndrome de Li-Fraumeni/fisiopatología , Ratones , Persona de Mediana EdadRESUMEN
Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.
Asunto(s)
Neoplasias Cerebelosas/genética , Genoma Humano/genética , Meduloblastoma/genética , Envejecimiento/genética , Secuencia de Aminoácidos , Transformación Celular Neoplásica , Neoplasias Cerebelosas/clasificación , Neoplasias Cerebelosas/diagnóstico , Neoplasias Cerebelosas/patología , Niño , Cromatina/metabolismo , Cromosomas Humanos/genética , ARN Helicasas DEAD-box/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Genómica , Proteínas Hedgehog/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Histona Demetilasas/genética , Humanos , Meduloblastoma/clasificación , Meduloblastoma/diagnóstico , Meduloblastoma/patología , Metilación , Mutación/genética , Tasa de Mutación , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Receptores Patched , Receptor Patched-1 , Fosfoproteínas Fosfatasas/genética , Poliploidía , Receptores de Superficie Celular/genética , Análisis de Secuencia de ARN , Transducción de Señal , Proteínas de Dominio T Box/genética , Factores de Transcripción/genética , Proteínas Wnt/metabolismo , beta Catenina/genéticaRESUMEN
Deregulation of signaling pathways and subsequent abnormal interactions of downstream genes very often results in carcinogenesis. In this paper, we propose a two-compartment model describing intricate dynamics of the target genes of the Wnt signaling pathway in medulloblastoma. The system of nine nonlinear ordinary differential equations accounts for the formation and dissociation of complexes as well as for the transcription, translation and transport between the cytoplasm and the nucleus. We focus on the interplay between MYC and SGK1 (serum and glucocorticoid-inducible kinase 1), which are the products of Wnt/ß-catenin signaling pathway, and GSK3ß (glycogen synthase kinase). Numerical simulations of the model solutions yield a better understanding of the process and indicate the importance of the SGK1 gene in the development of medulloblastoma, which has been confirmed in our recent experiments. The model is calibrated based on the gene expression microarray data for two types of medulloblastoma, characterized by monosomy and trisomy of chromosome 6q to highlight the difference between diagnoses.
Asunto(s)
Proteínas Inmediatas-Precoces/metabolismo , Meduloblastoma/enzimología , Modelos Biológicos , Proteínas Serina-Treonina Quinasas/metabolismo , Vía de Señalización Wnt , Humanos , Proteínas Inmediatas-Precoces/genética , Meduloblastoma/genética , Meduloblastoma/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of α-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro, as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma.