Identification and characterization of functional genomic elements associated with progression of low to high grade glioma: integrative study of genome and epigenome

• Grant number: 14/08321-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): September 01, 2014
• Effective date (End): February 28, 2018
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Houtan Noushmehr
• Grantee: Camila Ferreira de Souza
• Host 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): 16/15485-8 - Clinical biomarkers in central nervous system tumors, BE.EP.PD

Abstract

Glioma is a heterogeneous group of tumors whose aetiology, histomorphologic features, molecular signatures, clinical behavior, response to therapy, and prognosis are variable. Glioma accounts for around eighty percent of all primary brain cancers. Some low-grade gliomas tend to progress to lesions with higher grades of malignancy. Glioblastoma multiforme (GBM), considered a high grade (IV) astrocytoma, is the most frequent and aggressive brain glioma in humans. Glioblastoma is treatment refractory, and patients with GBM have a poor prognosis with an overall median survival time of less than 15 months, highlighting an urgent need to define tumor subtypes which can improve the development of second line treatments for relapsed tumors. Epigenetic aberrations accumulate during tumorigenesis. Genomic instability and overexpression of oncogenes may occur downstream of abnormal DNA hypomethylation. Conversely, hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is an important mechanism for gene inactivation in neoplastic cells. Markedly, Noushmehr and colleagues (2010) first characterized a CpG island methylator phenotype as a distinct subgroup of human gliomas on both molecular and clinical grounds. In this scenario, this project aims to integrate the next-generation sequencing technology with clinical data, by harnessing both in-house and proven bioinformatic tools and data available in public databases, to better understand how the epigenome influences the progression from low-grade gliomas to glioblastomas. This integrated analysis will help to define aberrantly functioning molecular pathways and new subgroups that may be of clinical importance and able to enlighten the contribution of DNA methylation changes to glioblastoma pathology. (AU)

Scientific publications

(6)

(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)

ALDAPE, KENNETH; AMIN, SAMIRKUMAR B.; ASHLEY, DAVID M.; BARNHOLTZ-SLOAN, JILL S.; BATES, AMANDA J.; BEROUKHIM, RAMEEN; BOCK, CHRISTOPH; BRAT, DANIEL J.; CLAUS, ELIZABETH B.; COSTELLO, JOSEPH F.; et al. Glioma through the looking GLASS: molecular evolution of diffuse gliomas and the Glioma Longitudinal Analysis Consortium. NEURO-ONCOLOGY, v. 20, n. 7, p. 873-884, JUL 2018. (16/15485-8, 14/08321-3, 15/07925-5)

MAZOR, TALI; CHESNELONG, CHARLES; PANKOV, ALEKSANDR; JALBERT, LLEWELLYN E.; HONG, CHIBO; HAYES, JOSIE; SMIRNOV, IVAN V.; MARSHALL, ROXANNE; SOUZA, CAMILA F.; SHEN, YAOQING; et al. Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 114, n. 40, p. 10743-10748, OCT 3 2017. (16/15485-8, 14/08321-3, 15/07925-5)

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; et al. 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. (14/03989-6, 16/15485-8, 16/06488-3, 14/08321-3, 16/12329-5, 16/01975-3, 14/02245-3, 15/07925-5)

MALTA, TATHIANE M.; SOKOLOV, ARTEM; GENTLES, ANDREW J.; BURZYKOWSKI, TOMASZ; POISSON, LAILA; WEINSTEIN, JOHN N.; KAMINSKA, BOZENA; HUELSKEN, JOERG; OMBERG, LARSSON; GEVAERT, OLIVIER; et al. Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation. Cell, v. 173, n. 2, p. 338+, APR 5 2018. (16/06488-3, 14/08321-3, 15/07925-5, 16/01975-3, 16/01389-7, 16/15485-8, 14/02245-3, 16/10436-9, 16/12329-5)

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. (16/06488-3, 16/15485-8, 14/08321-3, 16/12329-5, 16/10436-9, 15/07925-5, 16/01975-3, 14/02245-3, 16/01389-7, 16/11039-3)

CECCARELLI, MICHELE; BARTHEL, FLORIS P.; MALTA, TATHIANE M.; SABEDOT, THAIS S.; SALAMA, SOFIE R.; MURRAY, BRADLEY A.; MOROZOVA, OLENA; NEWTON, YULIA; RADENBAUGH, AMIE; PAGNOTTA, STEFANO M.; et al. Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma. Cell, v. 164, n. 3, p. 550-563, JAN 28 2016. (14/08321-3, 15/02844-7, 14/02245-3, 15/07925-5)