Integrative epigenomic analysis of high and low Glioma-CpG island Methylator Phenotype (G-CIMP): characterization and methods development

• Grant number: 16/06488-3
• Support type: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): May 01, 2016
• Effective date (End): March 31, 2018
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Houtan Noushmehr
• Grantee: Thaís Sarraf Sabedot
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 15/07925-5 - Open source software statistical tools to aid in analyzing and integrating large cancer epigenomic datasets in order to decipher and understand regulatory networks, AP.JP
• Associated scholarship(s): 16/12329-5 - Chromatin accessibility and DNA methylation changes associated with high and low Glioma-CpG island methylator phenotype (G-CIMP), BE.EP.DD

Abstract

Gliomas, including glioblastoma which is the most lethal intracranial tumor, exhibit a very complex development that can lead to treatment resistance and recurrences. This heterogeneity can interfere in the diagnosis and, therefore, in the therapeutic approach. Currently, gliomas are classified based on histology and then graded on a scale of I to IV, depending on the degree of malignancy. However, the histological features are generally inferred by pathologists' observation of a biological sample collected from the tumor, which can cause diagnostic discrepancies. This scenario has been changing for the past years with constant updates on the molecular profiling of gliomas and the advance of technologies that allow the enforcement of these results in the clinic. The most recent study about the genomic and epigenomic landscape of gliomas showed a distinct subgroup of IDH mutant samples with poor survival. This subtype (GCIMP-low) is characterized by a loss of DNA methylation, based on array data (Illumina HumanMethylation27 and HumanMethylation450), when compared to other IDH mutant samples also without codeletion of chromosomes 1p and 19q. (GCIMP-high). We propose to analyze the changes across the entire epigenome between GCIMP-low and GCIMP-high samples in order to identify candidate deregulated regions, thereby understanding progression among IDH mutant samples. The glioma samples will be acquired and processed using tools developed by our group, such as TCGAbiolinks (an R/Bioconductor package). Complementary epigenomic data including ChIP-seq and known regulatory elements from external databases (TCGA, ENCODE and Roadmap) in normal brain and non-brain and in tumor samples will be obtained by the development of a new tool called biOMICs+ which will allow data integration from different sources. The regulatory networks that we propose to identify in this project will be annotated, based on DNA methylation and gene expression profiles of glioma samples, and characterized to expand the knowledge of molecular basis of tumors, specially gliomas, with the aim of understanding mechanisms related to initiation and progression of brain cancer. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GARCIA-ROSA, SHEILA; TRIVELLA, DANIELA B. B.; MARQUES, VANESSA D.; SERAFIM, RODOLFO B.; PEREIRA, JOSE G. C.; LORENZI, JULIO C. C.; MOLFETTA, GREICE A.; CHRISTO, PAULO P.; OLIVAL, GUILHERME S.; MARCHITTO, VANIA B. T.; BRUM, DORALINA G.; SABEDOT, THAIS S.; NOUSHMEHR, HOUTAN; FARIAS, ALESSANDRO S.; SANTOS, LEONILDA M. B.; NOGUEIRA-MACHADO, JOSE A.; SOUZA, JORGE E. S.; ROMANO, CAMILA M.; CONDE, RODRIGO M.; SANTOS, ANTONIO C.; GUERREIRO, CARLOS T.; SCHREUDER, WILLEM H.; GLEBER-NETTO, FREDERICO O.; AMORIM, MARIA; VALIERIS, RENAN; DA SILVA, ISRAEL TOJAL; SILVA, JR., WILSON A.; NUNES, DIANA N.; OLIVEIRA, PAULO S. L.; VALENTE, VALERIA; ARRUDA, MARIA AUGUSTA; HILL, STEPHEN J.; BARREIRA, AMILTON A.; DIAS-NETO, EMMANUEL. A non-functional galanin receptor-2 in a multiple sclerosis patient. PHARMACOGENOMICS JOURNAL, v. 19, n. 1, p. 72-82, FEB 2019. Web of Science Citations: 2.

MALTA, TATHIANE M.; DE SOUZA, CAMILA F.; SABEDOT, THAIS S.; SILVA, TIAGO C.; MOSELLA, MARITZA S.; KALKANIS, STEVEN N.; SNYDER, JAMES; CASTRO, ANA VALERIA B.; NOUSHMEHR, HOUTAN. Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications. NEURO-ONCOLOGY, v. 20, n. 5, p. 608-620, MAY 2018. Web of Science Citations: 19.

DE SOUZA, CAMILA FERREIRA; SABEDOT, THAIS S.; MALTA, TATHIANE M.; STETSON, LINDSAY; MOROZOVA, OLENA; SOKOLOV, ARTEM; LAIRD, PETER W.; WIZNEROWICZ, MACIEJ; IAVARONE, ANTONIO; SNYDER, JAMES; DECARVALHO, ANA; SANBORN, ZACHARY; MCDONALD, KERRIE L.; FRIEDMAN, WILLIAM A.; TIRAPELLI, DANIELA; POISSON, LAILA; MIKKELSEN, TOM; CARLOTTI, JR., CARLOS G.; KALKANIS, STEVEN; ZENKLUSEN, JEAN; SALAMA, SOFIE R.; BARNHOLTZ-SLOAN, JILL S.; NOUSHMEHR, HOUTAN. A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence. CELL REPORTS, v. 23, n. 2, p. 637-651, APR 10 2018. Web of Science Citations: 21.

MALTA, TATHIANE M.; SOKOLOV, ARTEM; GENTLES, ANDREW J.; BURZYKOWSKI, TOMASZ; POISSON, LAILA; WEINSTEIN, JOHN N.; KAMINSKA, BOZENA; HUELSKEN, JOERG; OMBERG, LARSSON; GEVAERT, OLIVIER; COLAPRICO, ANTONIO; CZERWINSKA, PATRYCJA; MAZUREK, SYLWIA; MISHRA, LOPA; HEYN, HOLGER; KRASNITZ, ALEX; GODWIN, ANDREW K.; LAZAR, ALEXANDER J.; STUART, JOSHUA M.; HOADLEY, KATHERINE A.; LAIRD, PETER W.; NOUSHMEHR, HOUTAN; WIZNEROWICZ, MACIEJ; NETWORK, CANCER GENOME ATLAS RES. Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation. Cell, v. 173, n. 2, p. 338+, APR 5 2018. Web of Science Citations: 92.

MELISO, FABIANA M.; MICALI, DANILO; SILVA, CAMILA T.; SABEDOT, THAIS S.; COETZEE, SIMON G.; KOCH, ADRIAN; FAHLBUSCH, FABIAN B.; NOUSHMEHR, HOUTAN; SCHNEIDER-STOCK, REGINE; JASIULIONIS, MIRIAM G. SIRT1 regulates Mxd1 during malignant melanoma progression. ONCOTARGET, v. 8, n. 70, p. 114540-114553, DEC 29 2017. Web of Science Citations: 4.

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SABEDOT, Thaís Sarraf. Molecular classification of adult diffuse gliomas based on DNA methylation reveals subgroups of G-CIMP tumors associated with distinct clinical features. 2018. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto Ribeirão Preto.