The Cancer Genome Atlas (TCGA), the NIH research program that has helped set the standards for characterizing the genomic underpinnings of dozens of cancers on a large scale, is moving to its next phase.
TCGA was launched by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) in 2006 as a pilot project to comprehensively characterize the genomic and molecular features of ovarian cancer and glioblastoma multiforme. The program grew to include samples from 11,000 patients across 33 tumor types and represents the largest tumor collection ever to be analyzed for key genomic and molecular characteristics. Findings for 13 cancer types have already been published, and as of late 2014, TCGA scientists had nearly completed sequencing protein-coding regions (exomes) for most tumor types, and completed whole-genome sequencing (WGS) for 1,000 tumor samples. The latter characterizes the complete DNA sequence in the genome. Results from TCGA analyses to date have led to more than 2,700 articles in research journals.
“TCGA was the project that needed to be done; there had to be a large scale profiling of tumors to figure out the genetics of cancer,” said D. Neil Hayes, M.D., associate professor, hematology/oncology, University of North Carolina, Chapel Hill, and a co-principal investigator of the TCGA project to characterize head and neck cancers.
Importantly, most of the funding for TCGA came from the 2009 American Recovery and Reinvestment Act (ARRA) and did not divert any of the funding that helped fund ongoing and future research grants. Indeed, the ARRA funding probably enabled TCGA to explore more cancer genomes than would have been possible with just traditional funding allocations.
“Every paper has shown novel mutations and helped explain pathways and mechanisms in cancer development and its growth and spread,” Hayes said. “These papers have helped focus our research efforts and suggested new directions for therapy. The work also dovetails with increased use of clinical sequencing on cancer patients that we are beginning to see in some places. Many of these centers are turning to TCGA data and analyses to make this possible.”
TCGA’s success inspired another project: the International Cancer Genome Consortium (ICGC). This organization, launched in 2008, coordinates over 70 international research projects across five continents with the shared goal of generating a comprehensive catalog of genomic abnormalities in cancer. TCGA is a core data and analysis contributor to ICGC, providing about 60 percent of the patient data housed in ICGC’s Data Coordination Center.
While TCGA sample collection ended in 2013, the data continue to be analyzed and papers continue to be published in scientific journals. If TCGA data can be considered a foundation on which further research and pharmaceutical development can be built, their use in the clinic remains a work in progress.
New Projects: PanCanAtlas, PCAWGs, and CDDP
TCGA is building upon the success of its Pan-Cancer Analysis, published in Cell in August 2014 and on Nature’s TCGA microsite in 2013. The depth and breadth of TCGA's extensive characterization of cancer genomes allowed a cross-cancer analysis over multiple data platforms, resulting in the Pan-Can analysis. This research showed that some cancer subtypes may be more similar to each other than to others from the same organ-of-origin. They also might share common genetic features that could be susceptible to some targeted therapies on the market, but not yet considered for the particular subtype. In other words, seemingly dissimilar cancer types may share a vulnerability for which a drug is already available.
To expand on the TCGA's Pan-Cancer Analysis, two new projects are underway: PanCanAtlas and Pan-Cancer Analysis of Whole Genomes (PCAWGs). PanCanAtlas takes advantage of the additional data generated by TCGA since the original Pan-Cancer project, which examined 12 tumors types. PanCanAtlas expands on this project by analyzing data from all TCGA tumor types. These additional data will allow researchers to discover even more complex relationships across cancer types.
PCAWGs is a collaboration with ICGC to analyze whole genome data from 2,000 pairs of tumor and normal samples and integrate the results with clinical and other molecular data available on those same cases. Investigators from around the world will lead working groups in the analysis in a number of scientific areas, such as mutation identification algorithms and patterns of structural variation in genomes. The data generated by whole genome sequencing will enable researchers to develop and examine a variety of hypotheses.
The Future of Genomics Research within the Center for Cancer Genomics
TCGA is part of the Center for Cancer Genomics (CCG) at NCI, which combines many genomic research activities. In CCG, TCGA joins projects that complement the data generated to date. Two examples are Exceptional Responders, a project to identify genomic changes in patients who respond remarkably well to treatments that fail most patients, and ALCHEMIST, a clinical trial to find mutations in early stage lung cancer patients and evaluate drug treatments designed to improve clinical outcomes. TCGA's comprehensive genome characterization pipeline will be used to analyze samples in these studies.
One other program that is kicking off is the Cancer Driver Discovery Project (CDDP), which aims to characterize driver genetic events that occur in two percent or more cases of three common tumors: lung adenocarcinoma, colorectal cancer and ovarian cancer. Many of these cases will be drawn from completed NCI clinical trials, allowing the program to determine if molecular features of the tumors influenced the therapeutic response.
“We can declare quite a few successes from TCGA based on our great sample collection and comprehensive molecule analysis, which has allowed us to identify genetic drivers of some cancers at frequencies as low as 5 to 10 percent.” said CCG Director, Louis M. Staudt, M.D., Ph.D. “TCGA has led to an appreciation of cancer pathways that weren't even considered 5 or 10 years ago. The program has created a basis for exciting future research and the CCG will carry the torch forward to fulfill TCGA's original goal: to improve our ability to diagnose, treat and prevent cancer."