Proteogenomics: a research rocket ship for the Cancer Moonshot.
The Cancer Moonshot is a challenge to double the rate of progress in cancer treatment and research. What will it take to achieve success?
This effort will need a map--the DNA. It will need a delivery vehicle--the RNA transcripts of the DNA. But most of all the Cancer Moonshot will need a destination--the proteins that actually make cancer happen.
This national roadmap to dramatic progress in cancer research will also need a way to understand the connections among the genes, the transcripts, and the proteins. That means joining forces around the globe to stop this dreadful disease. The Cancer Moonshot will require integrating tremendous amounts of information to understand both the fundamental drivers of cancer and the individual nuances of how the disease manifests itself, and responds--or fails to respond--to therapy.
All these imperatives mean employing new research concepts. One is proteogenomics.
Although the word may not be familiar, proteogenomics is the foundation of something intensely personal: precision medicine, an approach to medical care that uses precise information about the genes and proteins in an individual persons tissues, both healthy and diseased, to inform individual treatment options. It acknowledges a persons uniqueness, rather than relying on broad categories based on the behavior of populations.
The Cancer Moonshot itself is based on a precision approach to the entire spectrum of cancer, from detection and diagnosis, to prognosis and therapy.
The search for protein function
The genes in our DNA are only the beginning of what happens in our bodies. What really counts is function--what cells actually do. The potential encoded in the genome is executed by proteins. In turn, protein function is regulated by small molecular change known as posttranslational modifications, which cannot be detected in the DNA or RNA.
Cancer is initiated by changes in our DNA. But the real damage is done by proteins that cause cancer cells to misbehave. The cells grow when they should not and they aggressively invade tissues where they should not.
Researchers need a way of understanding those rogue proteins. That's where proteogenomics shines. As a fusion of proteomics and genomics, it's a way to generate hypotheses from genomic observations, which are then tested at the protein level. To interpret protein abundance and protein modifications, researchers are guided by their knowledge of the actual genome in the specific cells and tissues under investigation.
In the past decade, a revolution in DNA sequencing technology has led to an explosion of information about the human genome. In turn, the availability of next-generation sequencing technologies has fueled comprehensive analyses of the human genome and transcriptome, such as The Cancer Genome Atlas (TCGA).
For research on specific types of cancer, large-scale analytical efforts have provided novel insights into the association of chromosomal rearrangements, DNA copy number alterations, somatic mutations, and RNA splicing variants with cancer. All of this underscores the concept that cancer is not one disease, but thousands of diseases.
In some ways, NextGen sequencing has provided too much information--so much data that it is difficult to know what changes drive cancer, and which changes are mere passengers on the road to cancer. Measuring the proteins involved make it much easier to hone in on the changes that are most influential in determining the outcome of the disease. This is especially true of the post-translational modifications that switch proteins on and off, such as phosphorylation, glycosylation, and acetylation.
Benchmarks and standards
Because proteins are central to how cancer happens in our bodies, the National Cancer Institute established the Clinical Proteomic Technology Assessment Consortium (CPTAC) in 2006 to establish a set of rigorous and broadly recognized standards for the proper execution of proteomic experiments in a clinical context. It also established a path to standards of reproducibility and accuracy associated with clinical testing labs and Clinical Laboratory Improvement Amendments (CLIA) certification.
In short, CPTAC requires scientists to make sure their labs work from the same playbook when it comes to understanding the activity of proteins in people.
In another advance, mass spectrometry platforms, the workhorses of proteomics, were benchmarked against a defined set of samples. That resulted in two foundational reports demonstrating the reproducibility and robustness of mass spectrometry measurements across multiple laboratories, and including both "discovery" and "targeted" analyses.
Equipped with this suite of standardized workflows and quality control procedures, CPTAC morphed into the Clinical Proteomic Tumor Analysis Consortium, which goes by the same acronym. The redefined CPTAC focused on providing comprehensive and quantitative analyses of the same exact tumors analyzed by TCGA.
The first three tumor types analyzed by the consortium were colorectal, breast, and ovarian. The resulting three flagship reports provided a substantial resource to the cancer research community by documenting which DNA and RNA changes carried through to the protein level, allowing researchers to focus on those changes with the greatest functional impact. The reports also provided new insights into the substantial effects of post-translational modifications, specifically phosphorylation and acetylation, on the functional activities associated with DNA repair, proliferation, and survival.
CPTAC continues to define the most rigorous standards for proteomic experiments. For example, CPTAC scientists realized that the time between disruption of blood flow to a sample and flash freezing (the warm ischemia time) had a significant effect on the observed phosphorylation of proteins in a few key pathways associated with stress responses. Now the warm ischemia time for all CPTAC tumor samples is tightly controlled and accurately reported.
The power of teamwork
A key contribution of CPTAC is the collaborative nature of the consortia, and the open communication among the participating components. A third iteration of CPTAC now integrates Proteomic Characterization Centers--which are tasked with the analysis of five new cancer types and the development of a minimum of 1,000 targeted assays; Proteogenomic Data Analysis Centers--which develop and apply novel approaches for extracting maximal information from proteogenomic data; and Proteogenomic Translational Research Centers--which apply proteogenomic analyses to samples obtained from patients participating in active NCI-sponsored clinical trials.
To beat cancer we need many minds from many disciplines working together. All this fruitful crosstalk and data sharing among investigators produces synergies in analysis and interpretation, technology development, and experimental design. Those synergies could fulfill the stated aims of the Cancer Moonshot.
What will the cancer research landscape look like in five years? Ideally, fewer people will die from cancer because their disease will be detected earlier, and treated more effectively. But a few advances are still needed:
* For early detection, new protein-based biomarkers from non-invasive sampling of body fluids.
* Personalized cancer pathway maps for every patient. They would identify the key intersections where a targeted drug can not only halt a tumor's spread, but reverse the process.
* Sensitive methods for measuring and assessing therapeutic response. This would allow patients to quickly transfer to new treatment regimes as a tumor evolves to evade treatment. Precious time would not be lost on the wrong therapy.
All of these advances (and more) are possible when genome scientists, proteome scientists, clinicians, and data analysts work together for prevention as well as treatment. Such collaboration integrates the wealth of data new technologies provide, and helps cancer clinicians apply new insights to each of us individually.
--Karin Rodland, Ph.D. Chief Scientist for Biomedical Research, Director of Biomedical Research Partnerships, Pacific Northwest National Laboratory
Caption: Karin Rodland, Ph.D., in her lab at Pacific Northwest National Laboratory. Credit: Pacific Northwest National Laboratory
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|Title Annotation:||LIFE SCIENCE|
|Publication:||R & D|
|Date:||Jun 1, 2017|
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