Generating the Genome: How Scientists Changed the Face of Cancer ResearchGenerating the Genome: How Scientists Changed the Face of Cancer Research https://pediatricsnationwide.org/wp-content/uploads/2018/09/ElaineMardisRichardWilson.gif 1024 683 Katie Brind'Amour, PhD, MS, CHES Katie Brind'Amour, PhD, MS, CHES https://pediatricsnationwide.org/wp-content/uploads/2021/03/Katie-B-portrait.gif
- September 11, 2018
- Katie Brind'Amour, PhD, MS, CHES
Team science. Ongoing innovation. Brilliant minds. Here’s how The Cancer Genome Atlas spawned a revolution in cancer research and technology.
The Cancer Genome Atlas is wrapping up. Its data now lives online in the Genomic Data Commons, freely available to the public. Reports of the primary findings for each studied tumor type have been published, and summaries of the key themes uncovered during the 10-year project make up the Pan-Cancer Atlas.
The project’s ambitious efforts are nearly complete, but its impact is just beginning. The Cancer Genome Atlas has made waves that will carry a wealth of discoveries to the world’s future cancer patients.
A Noble Effort, With Notable Results
Conceived as the Human Genome Project wound down, The Cancer Genome Atlas (TCGA), a collaboration between the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), became the answer to scientists’ quest to apply what they had just learned to a new frontier: human disease.
“We had finished sequencing the human genome and thought, ‘How do we apply this to understanding disease?’” says Richard Wilson, PhD, executive director of the Institute for Genomic Medicine (IGM) at Nationwide Children’s Hospital and one of the original collaborators in TCGA. At the time, he and another early TCGA collaborator, Elaine Mardis, PhD, co-executive director at IGM, ran the McDonnell Genome Institute at Washington University – St. Louis — a key player in the Human Genome Project and one of the country’s most advanced genomics centers. “With the technology and infrastructure developed in the Human Genome Project, we knew we could potentially take a new approach to understanding the genomic contributors to cancer development.”
Their team was already sequencing genes they thought were involved in acute myeloid leukemias (AML) and lung cancers. Their efforts grew and coincided with activities at other large genome centers performing a wide range of tissue analysis and tumor characterization work.
In time, the NHGRI and NCI expressed interest in expanding the efforts of these advanced teams, and TCGA was born in 2005. With the advent of next-generation sequencing technology a few years later, however, TCGA was transformed.
“Next-generation technology allowed us to scale up and move from a targeted list of relatively few cancer genes to all genes — the ‘exome’ — and potentially whole genome sequencing,” says Dr. Wilson. “It ultimately had a huge impact on the rate of discovery for TCGA.”
Researchers began sequencing the entire genome for groups of patients with particular cancer types, such as leukemia or breast cancer.
“The data was a treasure trove for understanding the biology of those cancer types, what mutations drive them, how to better treat them. But for me the most incredible thing that came out of TCGA was that sometimes the tissue of origin didn’t matter,” Dr. Wilson says. “Lung, breast, brain tumors — often they’d have the same mutations in the same genes. So instead of asking ‘How do we treat a breast tumor?’ we could ask ‘How do we treat an HER2 tumor, or a p53 tumor?’”
This broad collection of cancer genome details produced by TCGA scientists now serves as a resource for researchers — a literal atlas of cancer alterations. TCGA data are now shown as the gold standard comparator in cancer presentations and publications.
“TCGA allowed us to use new computational analysis of the data to flesh out a valuable reference tool,” says Dr. Mardis, who joined Nationwide Children’s together with Dr. Wilson in 2016 after years of their involvement in high-profile genomics initiatives such as TCGA, the 1,000 Genomes Project and the Human Microbiome Project. “Now scientists can apply the knowledge and underpinnings from TCGA to learn more about each individual cancer patient’s DNA — plus how DNA changes bear out at the level of RNA and proteins — to give the context of what’s driving each person’s specific cancer.”
The Science Behind the Story
Next-generation sequencing wasn’t the only advancement that made a broad impact on modern genomics. The science of sample processing also advanced in leaps and bounds, due in a large part to the concerted efforts of biospecimen processing laboratories involved in TCGA and other large-scale tissue-based research endeavors.
“When TCGA started, one of the biggest limitations was the availability of high-quality tumor samples from patients, and many didn’t have much clinical information attached,” says Dr. Wilson. “And if you can’t get high-quality samples, you won’t get very far trying to understand human disease.”
Enter the Biospecimen Core Resource (BCR) in The Research Institute at Nationwide Children’s. Led by Principal Investigator Julie Gastier-Foster, PhD, and Lead Pathologist Nilsa Ramirez, MD, the BCR began processing samples and conducting pathology review in 2009 for the National Cancer Institute’s Center for Cancer Genomics projects, including TCGA. They joined TCGA’s original biospecimen center, the International Genomics Consortium (IGC), to offer additional specimen characterization support and enable project expansion.
“We got involved in improving methodologies to try to get the highest quality data out of tissue specimens that came in,” says Dr. Gastier-Foster. “At the time, TCGA was challenged by high failure rates due to problematic tissue types. We worked with IGC and NCI to develop methods to address those problems and introduced different processing methodologies.”
As part of their own quality and process improvement efforts, the BCR team continually refined and improved sample quality, the attached breadth of clinical information, quality control and extraction of useful material from the samples for shipment to the genomic analysis centers.
“The Nationwide Children’s Biospecimen Core Resource truly made a huge difference in the ability of TCGA to scale up, to process a lot more samples and to produce very high-quality data for a lot of different tumor types,” says Dr. Wilson.
TCGA wasn’t the only cancer research effort to benefit from the Biospecimen Core Resource’s precision. The biorepository, housed within the Biopathology Center (BPC) at Nationwide Children’s, has stored and processed samples for adult and pediatric cancer research groups for decades, including the Children’s Oncology Group (COG), Southwest Oncology Group (SWOG), NRG Oncology and research teams from within the hospital.
We’re working hard to blur the line between basic research and clinical genomics.
— Richard Wilson, PhD
In particular, the BCR and the BPC have enabled more informed biospecimen processing support and storage for the hospital’s Institute for Genomic Medicine, which houses both clinical and basic science programs.
“We’re working hard to blur the line between basic research and clinical genomics,” says Dr. Wilson. “We’ve succeeded in gaining support from hospital leadership and the institutional review board to make that happen. It’s an exciting and unique feature of our program.”
Most genomics facilities have separate research and clinical programs, but at Nationwide Children’s, the institute’s clinical laboratory, computational genomics, genomic services laboratory, technology development group and translational research programs all fall under the same umbrella. These groups collaborate to focus on more than just DNA.
“What TCGA did that a lot of genomics studies still don’t do was to look at the tumor in many different ways,” says Jay Bowen, program director of the BCR at Nationwide Children’s. “They began to study not only the DNA sequence to see what’s potentially driving a cancer but also the RNA and proteins, and determine whether what’s in the DNA actually has an impact on how the cancer operates. Now, our own genomics experts can also look at a tumor from a 360-degree view.”
Creating the Future of Cancer Treatment
Integration of a wealth of scientific genomic data with clinical expertise in patient cancer care is still fairly new territory, but it is the direction many genomics experts believe the field is headed. With that goal in mind, IGM already facilitates a novel collaboration.
“Our Cancer Protocol is aimed at trying to move genomics into direct patient care. We designed it to better understand the genomics of the patient’s tumor and to have a means to make some genomics studies available to patients prior to them being fully reimbursed or available on a clinical basis,” says Dr. Gastier-Foster, who is also senior director of the IGM Clinical Laboratory at Nationwide Children’s. “It’s not a pure research or a pure clinical protocol — it’s a blend.”
The Cancer Protocol, developed by IGM’s leadership team, reviews patient nominations for genomic profiling submitted by hospital oncologists. In most cases, the nominees have tumors that did not respond to prior rounds of therapy or that came back after remission. Selected patients are invited to consent to have a full genomic analysis performed.
“Many centers utilize a small gene panel or test about 100 to 500 genes,” says Dr. Mardis, who is also president-elect of the American Association for Cancer Research for 2018-2019. “We look at both tumor and normal cells for all patients and do a thorough comparison across all known human genes. We look for susceptibility genes for their cancer risk by studying normal cells, and we look across the entire cancer genome plus their RNA for clues to what might be driving their cancer. That level of comprehensive study is not very common.”
Although this is still a research-based study, the team identifies potential clinically important findings that are then subjected to existing clinical testing options. By doing so, if they validate the findings, the relevant clinical information can be recorded in the medical record and, ideally, may identify alternative treatment options or offer a clue to likely outcomes.
The more results they validate and link to relevant clinical interpretations, the closer they get to offering the comprehensive testing as a clinical test, allowing them to bring genomics into frontline availability for care. Insurance reimbursement is expected to lag, but IGM leadership anticipate having some options approved for insurance reimbursement as soon as the end of 2018.
Another byproduct of genomic research projects such as TCGA is, unfortunately, the widespread perception of genomic sequencing as cost-prohibitive. In its infancy, sequencing could cost a million dollars per patient.
Fast forward a decade, however, and large sequencing tests and tumor analyses can be done for a few thousand or less. Not only can the technology cost less than new cancer drugs, but it may also have the potential to save patients the harm or lost time from poorly targeted therapies.
Aside from the financial considerations, genomics has logistics hurdles that researchers also intend to address.
“We’re constantly refining our understanding of what combinations of mutations lead to cancer. It can literally be a different equation for every patient,” says Dr. Mardis. “That presents a challenge for small practices and community hospitals. Even once patients and physicians are aware that these tests are available and understand what insights they can offer, there’s an access barrier for interpretation of genomic test results.”
Regardless of the challenges for reimbursement and access, many genomics experts are optimistic about the future use of genomics in cancer diagnostics and clinical decision-making.
“We want to get to the point where a comprehensive genome analysis is available to every patient that comes here with a cancer diagnosis,” says Dr. Wilson. “To get there, we have to work out how to do the analysis quicker and cheaper and how to help physicians understand what to do with it. It’s a question of building the infrastructure to make it more widespread.”
The Next Wave of Discovery
As IGM chips away at the clinical and translational research angle, the BCR aims to expand the options available for genomic research and testing by bringing an entirely new set of tissue samples into the mix: traditional paraffin-embedded and archival tissue samples. These classic specimen preservation and storage methods, widely used at hospitals and other biobanks, are often not suitable for genomics research. The BCR team has worked to optimize methods for extracting usable DNA/RNA and related subcellular matter so that innumerable specimens from facilities around the world could become rich sources for additional genomics research and clinical care, both in cancer and other diseases.
For the Children’s Oncology Group, the BPC has already begun to test previously unusable tissue samples to provide clinicians with treatment and prognosis information, with efforts underway to enable a full-blown genomic diagnostic work-up using their new methods.
And novel uses for challenging specimen types are just the beginning. The BCR has received a $4.5 million federal contract — with the potential to receive more than $49.9 million over five years — to receive, process, monitor quality and distribute tumor derivatives. In doing so, the BCR will further develop its key processing and analysis role in a national network of large-scale cancer genomic projects.
“I think people are beginning to realize the importance of biorepositories. These kinds of critical genomics projects couldn’t occur if we didn’t have highly annotated, high-quality specimens in banks like ours,” says Dr. Gastier-Foster. “They are leading to the next discovery. If people aren’t banking tissues, we can’t add new answers.”
As the Biospecimen Core Resource, the Institute for Genomic Medicine, the NCI Center for Cancer Genomics and the entire system of genomics-focused research and clinical groups continue to refine the logistics and technology behind cancer genomics, continued advancement in its clinical applications should cement the role of this transformational science in the field of oncology.
Built on a solid foundation of TCGA-generated, open-source data, the field of cancer genomics has a rich future ahead of it — and today’s patients are already benefitting from its legacy in the making.
This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN261201700015I.
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