RIBEIRAO PRETO, SP, BRAZIL (January 28, 2016) – Cell publishes on its January 28th edition the results of the largest study ever performed on the molecular profiles of gliomas – that represent 80% of tumors of the central nervous system. Three research groups from Ribeirão Preto Medical School (FMRP) at the University of São Paulo (USP), Brazil, Columbia University Medical Center (CUMC), USA, and the University of Texas MD Anderson Cancer Center, Houston, Texas, USA, co-led the investigation. They analysed samples from 1122 different glioma cells and compared the results to the clinical outcome of patients. The study led to discoveries about the presence and the combination of different molecular indicators which allow more accurate prediction of patients' prognoses.
The article, entitled Molecular profiling refines the classification of adult diffuse lower- and high-grade glioma, proposes seven categories for the tumor progress assessment. Currently, gliomas are classified in four different degrees, according to the appearance of the cells under a microscope. MRI and clinical data complement the diagnosis. The present classification does not work well for tumors of intermediate severity. "We established the complete set of genes associated with gliomas and used molecular and genomic techniques to provide new insights into prognoses", said co-senior author Houtan Noushmehr, PhD, professor of epigenomics and bioinformatics at University of São Paulo, Brazil, and director of the OMICs and Bioinformatics lab at FMRP, São Paulo, Brazil. Dr Noushmehr and his team led the epigenetic analysis of this project. "We discovered low grade and high grade gliomas mixed together within these different epigenetic subtypes. This was an unexpected finding and allowed us to further understand the progression of gliomas within the different subtypes," said Dr. Noushmehr.
"By looking at the molecular makeup of these tumors, we now have a much more precise way of predicting which tumors are more likely to grow rapidly and can prescribe treatments accordingly.", said co-senior author Antonio Iavarone, MD, professor of neurology and pathology and cell biology (in the Institute for Cancer Genetics) at CUMC and a member of the Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian /Columbia University Medical Center. They led the clinical and genetic expression analysis.
"These findings are an important step forward in our understanding of glioma as discrete disease subsets, and the mechanism driving glioma formation and progression." said senior co-author Roel Verhaak, PhD, associate professor of bioinformatics and computational biology at University of Texas. "This study has expanded our knowledge of the glioma somatic alteration landscape and emphasized the relevance of DNA methylation profiles as a method for clinical classification", he added. The MD Anderson Cancer Center performed analysis related to samples chromosomal characterization.
Epigenetics and DNA methylation
DNA methylation is a biochemical reaction frequently found in cancer cells that prevents the activation of the gene next to it. It differs from genetic mutation – in which the change in the DNA chain occurs within the gene – that's why it is called an "epigenetic" mechanism. For gliomas, researchers have related DNA methylation levels with the development of tumors.
Omics Laboratory, coordinated by Houtan Noushmehr, has expertise in DNA methylation. "Omics" is a reference to the suffixes of genomics, proteomics, and epigenomics. The latter is the study of distinct modifications to the DNA which defines the regulation of genes in particular types of cell or tissue. "The epigenomic data defined by profiling DNA methylation levels for each of our samples allowed us to determine with accuracy which patient will present the best clinical outcome and the worst," said Dr. Noushmehr.
Other indicators involved in novel classification are the presence or absence of mutation in a gene called IDH and the presence or absence of changes in chromosomes of tumors.
Impact on clinics
The classification of gliomas in grades I, II, III and IV based on the appearance of tumor cells is well established and presently adopted by WHO. However, oncologists observed that some patients with tumors considered low degree rapidly succumb to the disease while others with more aggressive tumors in fact survive for several years. The article's findings explain this divergence, allowing for a more precise distinction between tumors, especially the ones in II and III grades. Because the diagnosis determines the type and intensity of treatment, the relative lack of precision in the diagnosis leads to the prescription of inappropriate treatment.
Glioma grades II, III and IV are presently incurable. Treatment combines surgery, chemotherapy and radiotherapy.
This study was supported by grants from the São Paulo Research Foundation (FAPESP) (2015/07925-5, 2015/02844-7, 2014/08321-3, 2014/02245-3), the National Institutes of Health (U24CA143883, U24CA143858, U24CA143840, U24CA143799, U24CA143835, U24CA143845, U24CA143882, U24CA143867, U24CA143866, U24CA143848, U24CA144025, U54HG003067, U54HG003079, U54HG003273, U24CA126543, U24CA126544, U24CA126546, U24CA126551, U24CA126554, U24CA126561, U24CA126563, U24CA143731, U24CA143843, P30CA016672, P50 CA127001, R01 CA190121, P01 CA085878), and the Cancer Prevention & Research Institute of Texas.
The researchers have submitted a patent for probes that can be used to predict a glioma's clinical outcome. The researchers declare no other conflicts of interest.
Ribeirao Preto Medical School (FMRP) at University of São Paulo (USP) provides excellence in patient care and in higher education, by training health professionals with a high level of qualification and qualified researchers in its graduate programs, which produce high-quality innovative research with international insertion. In this context, OMICs Lab aims to identify and understand the epigenomic signatures that define normal and disease states. The ultimate goal is to help develop better therapies and cures for complex diseases such as diabetes and cancer. To this end, we generate (by our own and through our collaborators), next generation sequencing data across a multitude of -omics type data, genomics, epigenomics, proteomics and transcriptomics and perform mechanistic studies. A main focus of the lab is to train and educate the next generation of scientists skills in analyzing and interpreting these data types and by doing so we introduce important skills in the scientific method, bioinformatics and leadership. For more information, visit http://www.fmrp.usp.br, http://www.usp.br or bioinformatics.fmrp.usp.br and find us on Facebook, Twitter and YouTube.
Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.
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