A Journey Towards Personalized Medicine #ISMBECCB #ISMB2017
Personalized medicine: what is it and why is it important? The simplest explanation is that every individual is different and every individual’s susceptibility to disease is different. A drug to treat disease X might work for patient A but might not work for patient B, because every patient’s molecular makeup is different. When it comes to cancers, which are groups of diseases characterized by various genetic and epigenetic alterations, it is immensely important to design therapies based on tumor genetic and epigenetic makeup to provide the best possible treatment.
Dr. Christoph Bock, principal investigator at Ce-M-M, Vienna, and winner of the 2017 ISCB Overton Award, started his keynote presentation at ISMB by demonstrating the importance of personalized medicine in various disease entities. The data published in Schork, 2015, clearly indicates that most of the available drugs for major diseases are helping a fraction of patients.
How can we overcome this and treat every patient effectively? The answer lies in “understanding the genetic and epigenetic makeup of each individual patient”. Though current sequencing technologies have accelerated the basic biological research, we have not yet reached a stage where designing therapies based on individual’s genetic and epigenetic makeup is feasible. However, we can stratify patients into subgroups based on genetic and epigenetic similarities.
What are the most important factors in developing personalized medicine?
In Dr. Bock’s opinion, one key factor is “bioinformatics methods”. Researchers and hospitals are generating large scale multiomics data at different points of the disease progression. The major challenges lie in integrating different data types in order to understand the heterogeneity and to propagate prediction confidence.
What is the role of non-genetic contributors of cancers in personalized medicine?
Genetic mutations are one of the first alterations to look at in any type of cancer to explain the clinical variability of different tumors of a cancer entity. Methods of analyzing the genetic mutations in order to understand the tumor progression are well established. But what about a cancer that carries very minimal mutations e.g. pediatric brain tumors, Ewing sarcoma etc.? How can one explain tumor progression and observed phenotypic differences? One possibility is to look at the epigenetic heterogeneity.
DNA methylation is an epigenetic mechanism by which cells carry ‘memories’ of their origin throughout their life. Understanding the DNA methylation differences of tumors and their normal equivalent cells and cell-types is of interest to cancer researchers as they seek to better understand the tumor cell characteristics and to design treatment therapies. DNA methylation data generated through Whole Genome Bisulfite sequence or 450k array technology is gaining attention to stratify tumors into subgroups. This is due to the fact that DNA methylation of tumor cells reflect their ancestor’s methylation patterns, which enable cancer researchers to stratify tumors into various epigenetic subgroups with different cell-of-origins. Below is a visual representation of Waddington landscape to demonstrate how DNA methylation is inherited into different cells from their parent cells.
Recent studies on Ewing sarcoma (Sheffield et al. 2017) and pediatric medulloblastoma (Northcott et al. 2017) are two examples which take advantage of DNA methylation data and stratified tumors into different subgroups. These are major steps towards personalized medicine; clinicians will now be able to design different therapies that work better for each of the subgroups instead of treating cancer as a whole.
The complexities of “cancers of unknown primary origin”
We know that cancer is a metastatic disease, and in most cases it is difficult to diagnose cancer in the early stages. The undiagnosed cancers progress to later stages and spread to different organs of the body. When a tumor is diagnosed in a different organ other than its primary origin, it is challenging to treat and arrest the spreading of the tumor from the primary site. The question here is how to detect the primary origin. Again the solution lies in comparing the epigenetics of the tumor detected in different organs and with non-tumor counterparts of the tumor tissues. It is not always possible to collect the normal corresponding of the same tissue as tumor, for example, brain tumors. We need a reference epigenome; not one, but many — a reference for thousands of cell-types present in human body. To establish this, the following organizations have been established worldwide and are working towards an understanding of the relevance of epigenetic differences in human diseases:
- International Human Epigenome Consortium
- ROADMAP Epigenomics Project
- BluePrint Epigenome
- CREST — IHEC
- Canadian Institute of Health Research
Technologies are growing fast, and many research centers are working restlessly to develop methods and technologies towards personalized medicine. Some countries are participating in organizations like ICPerMed and All of Us. Many, if not all, should take initiative and support organizations working in the direction of personalized medicine.
Suggested further reading:
- Schork, Nicholas J. 2015. “Personalized Medicine: Time for One-Person Trials.” Nature 520 (7549): 609–11
- Sheffield, Nathan C., et al. 2017. “DNA Methylation Heterogeneity Defines a Disease Spectrum in Ewing Sarcoma.” Nature Medicine 23 (3): 386–95
- Northcott, Paul A. et al. 2017. “The Whole-Genome Landscape of Medulloblastoma Subtypes.” Nature 547 (7663): 311–17
Disclaimer: Any views expressed are those of the author, not necessarily those of PLOS.
