Tailor-made treatment for brain tumor through genetic profiling

Dr. Daniel Brat of Emory University, lead author of one of the new studies, said genotyping would remove tumor variables. Credit Donna Martin/Emory University
Dr. Daniel Brat of Emory University, lead author of one of the new studies, said genotyping would remove tumor variables. Credit Donna Martin/Emory University

With the advent of personalized medicine, our approach to treatment of disease has become more precise and targeted with the usage of advanced technology and informative tools.

Recently, two studies published in the New England Journal of Medicine (NJEM) have sought the aid of genetic mapping of brain tumors using next generation sequencing techniques. These studies were performed with samples from nearly 1,380 tumors extracting information from the exome, transcriptome, microRNA sequencing alongside DNA methylation, DNA copy number and protein arrays to establish genetic subtypes and categorization of tumor characteristics at the molecular level. The informational database generated through these studies can be utilized to customize therapy for patients and provide a new dimension to clinical trials.

One of the studies is The Cancer Genome Atlas (TCGA) study of adult diffuse “lower-grade” gliomas (Grade II and III) and the other is a complementary large-scale study of genetic alterations across a range of diffuse gliomas (Grade II, III and IV) led by the Mayo Clinic and the University of California, San Francisco (UCSF).

Gliomas are tumors of the glial tissue and comprise of roughly one third of the brain tumor cases. The low-grade gliomas (LGGs) are frequently observed in young adults and include astrocytomas, oligodendrogliomas and oligoastrocytomas. They can’t be eliminated completely through surgery owing to their highly invasive and diffuse nature. The tumor tissue which remains behind after surgery can further lead to disease recurrence and malignant spreading. The nature of these tumors can be inconsistent and unpredictable. LGGs can progress to Glioblastoma Multiforme (GBM) which is the highest grade (Grade IV) and most aggressive form of glioma, within a span of months or, can remain unaggressive for long periods as well.

After integrating data from 293 patient samples using unsupervised clustering analysis, the TCGA study focused on 2 genetic alterations i.e. IDH mutation and 1p/19q codeletion. The Mayo Clinic and UCSF group analysed 1087 samples of diffuse gliomas for the presence of IDH mutations, 1p/19q codeletion and TERT promoter mutations. The tumors were further categorized into subtypes depending on the combination of these genetic alterations. The 3 subtypes from each study had a great correlation with age, histopathological features, genetic profile and outcomes.

Patterns of tumor growth were correlated with their genetic profiles. Some of them had a slow growth rate which was ideal for chemotherapy alone and some warranted a combined chemo and radiation therapy. There were also tumors which took an aggressive course of growth and were associated with poor survival. But the researchers said that the only ray of hope for such cases was their early detection. Dr. Daniel J. Brat, vice chairman of pathology and laboratory medicine at Emory University and lead author of TCGA study said “These are people who so seek out clinical trials, so this is valuable information for them.”

Currently the treatment of these different types of gliomas includes clinical monitoring, chemotherapy, radiation therapy etc which varies according to the tumor grade, its tissue characteristics (histological class), extent of resection and the information provided by secondary testing. The data revealed by these new studies is more beneficial than what is traditionally obtained through histological analysis of the tumor tissue under the microscope since the latter cannot predict the highly variable clinical behavior or disease progression adequately. Also, tissue analysis is confounded by variability in the assessment made by different doctors.

A doctor’s judgment varies “depending on where you were trained, when, and by whom. By relying more extensively on genetic profiles, “all that variability will go away,” said Dr. Brat. The studies thus indicate that molecular profiling is going to be central to the diagnosis and prognosis of brain tumors and not complementary to other methods of analysis.