Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Epigenomic Evolution of Diffuse Large B-cell Relapse

ABSTRACT: Here we characterize an association between disease progression and DNA methylation in Diffuse Large B cell Lymphoma (DLBCL). By profiling genome-wide DNA methylation at single base-pair resolution in thirteen DLBCL diagnosis-relapse sample pairs, we show DLBCL patients exhibit heterogeneous evolution of tumor methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse–associated methylation signature converging on key pathways such as transforming growth factor beta (TGF-beta) receptor activity. We also observe decreased intra-tumor methylation heterogeneity from diagnosis to relapsed tumor samples. Relapse-free patients display lower intra-tumor methylation heterogeneity at diagnosis compared to relapsed patients in an independent validation cohort. Furthermore, intra-tumor methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse. Using ERRBS, we profiled genome-wide DNA methylation patterns of non-relapse DLBCL tumor samples at diagnosis, relaspe DLBCL patient samples at diagnosis and relaspe.

ORGANISM(S): Homo sapiens

SUBMITTER: Yanwen Jiang

PROVIDER: E-GEOD-66329 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC gene family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this molecular group died of rapidly progressive disease post-relapse. To study this genetic interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of Trp53 function in this model produced aggressive tumors that mimicked the characteristics of relapsed human tumors with combined P53–MYC dysfunction. Restoration of p53 activity, genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53–MYC interactions which emerge at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. There are currently no effective therapies for children with relapsed medulloblastoma. While clinical and biological features of the disease at diagnosis are increasingly well understood, biopsy is rarely performed at relapse and few biological data are available to guide more effective treatments. Here, we show that medulloblastomas develop altered biology at relapse which is predictive of disease course and cannot be detected at diagnosis. We have discovered the emergence of P53–MYC interactions at relapse, as biomarkers of clinically aggressive relapsed disease, which can be modelled and targeted therapeutically in genetically-engineered mice. These data provide clear precedent for the incorporation of biopsy at relapse into routine clinical practice, to direct palliative care and the development of improved treatment strategies. mouse model expression profiles from various mouse Medulloblastoma models MYCN/MYC overexpressing with/without p53 Mutations were compared to human MB expression profiles using Non-negative Matrix Factorization projection in order to sub-type the mouse models

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Epigenomic Evolution of Diffuse Large B-cell Relapse

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