The Cancer Genome Atlas (TCGA) is a project to catalogue genetic mutations responsible for cancer, using genome analysis techniques started in 2005.^[1][2] TCGA represents an effort in the War on Cancer that is applying recently developed high-throughput genome analysis techniques and is seeking to improve our ability to diagnose, treat, and prevent cancer through a better understanding of the molecular basis of this disease.

In 2006 the National Cancer Institute and the National Human Genome Research Institute selected people and laboratories that will participate in this project. The goal of the project was to provide systematic, comprehensive genomic characterization and sequence analysis of three types of human cancers glioblastoma multiforme, lung, and ovarian cancer.^[3]

The project is unique in terms of the size of the patient cohort interrogated (scheduled are 500 patient samples, far more than most genomics studies), and the number of different techniques used to analyze the patient samples. Techniques that are being used include gene expression profiling, copy number variation profiling, SNP genotyping, genome wide methylation profiling, microRNA profiling, and exon sequencing of at least 1,200 genes. Recently the group organizing the TCGA announced that they would sequence the entire genomes of some tumors and at least 6,000 candidate genes and microRNA sequences. This targeted sequencing is actively being performed by all three sequencing centers using hybrid-capture technology. A gene list is available on the TCGA website. In phase II, TCGA will perform whole exom sequencing on 80% of the cases and whole genome sequencing on 80% of the cases used in the project.

TCGA has expanded in 2009 from a pilot to a large scale project. Over the next 5 years TCGA will provide genomic characterization and sequence analysis on 20-25 different tumor types. In FY 2010 a number of new centers have been funded to characterize these new tumor types. There are Genome Characterization Centers (GCCs) and Genome Data Analysis Centers (GDACs) funded to move this project into the next phase. The fact that the RFA for the expanded phase of TCGA included the specific funding of these analysis cores reflects the growing need for dedicated funding to bioinformatics in these large scale programs.

Contents 1 Project Goals 2 TCGA Project Management 3 Tissue Accrual 4 TCGA Funding 5 Organization of the Project 6 List of Tumors and Entrance of a Tumor Type into TCGA 7 TCGA Groups Publish First Paper 8 See also 9 References 10 External links

[edit] Project Goals

The goal of the pilot project was to demonstrate that advanced genomic technologies could be utilized by a team of scientists from various institutions to generate statistically and biologically significant conclusions from the diverse genomic data set generated by the Project. Two tumor types were explored during the pilot phase, Glioblastoma Multiforma (GBM) and Cystadenocarcinoma of the Ovary. The goal of TCGA Phase II is to expand the success experienced in the pilot project to more cancer types, providing a large, statistically significant data set for further discovery. More information about TCGA is available at the TCGA home page (http://cancergenome.nih.gov/) and TCGA data can be accessed through the TCGA Data Portal (http://cancergenome.nih.gov/dataportal/data/about/).

[edit] TCGA Project Management

TCGA is co-managed by a team composed of scientists and managers from the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI). With the expansion of TCGA from the pilot phase to Phase II in October, 2009, the NCI created a TCGA Program Office. This office, directed by Joe Vockley, Ph.D., is responsible for the operation of six Genome Characterization Centers, seven Genome Analysis Centers, two Biospecimen Core Resource Centers, the Data Coordination Center and approximately one third of the sequencing done for the project by the three Genome Sequencing Centers. In addition, the TCGA Project Office is responsible for coordinating the accrual of tissues for the TCGA project. Brad Ozenburger, Ph.D., project manager from the NHGRI, directs two thirds of the sequencing at the Genome Sequencing Centers.

The Project is managed by a project team composed of members from the NCI (Anna Barker, Ph.D, Joe Vockley, Ph.D., Carolyn Compton, MD, Ph.D., Kenna Shaw, Ph.D. and Carl Schaffer, Ph.D.) and the NHGRI (Mark Guyer, Ph.D., Brad Ozenberger, Ph.D., Peter Good, Ph.D. and Jane Peterson, Ph.D.). This team, along with a group consisting of all principle investigators funded by the project, makes up the Steering Committee. The Steering Committee is tasked with overseeing the scientific validity of the project while the NCI/NHGRI project team ensures that the scientific progress and goals of the project are met, the project is completed on time and on budget and the coordination of the various components of the project.

[edit] Tissue Accrual

Tissue requirements vary from tissue type to tissue type and from cancer type to cancer type. Disease experts from the project’s Disease Working Groups help to define the characteristics of the typical tissue samples accrued as “standard of care” in the United States and how TCGA can best utilize the tissue. For example, the Brain Disease Working Group determined that samples containing more than 50% necrosis would not be suitable for TCGA and that 80% tumor nuclei were required in the viable portion of the tumor. TCGA has some general guidelines that it follows as a starting point for collecting samples from any types of tumors. These include a minimum of 200 mg in size, no less than 80% tumor nuclei and a matched source of germline DNA (such as blood or purified DNA). In addition, institutions submitting tissues to TCGA must have a minimal clinical data set as defined by the Disease Working Group, signed consents which have been approved by their institution’s IRB as well as a material transfer agreement with TCGA.

Recently, the NCI pulled approximately $130M of ARRA from the NCI’s “Prime Contract” with Science Applications International Corporation (SAIC) to fund tissue accrual and a variety of other activities through the NCI Office of Acquisition. $42M is available for tissue accrual through the NCI using “Requests for Quotations” (RFQs) and “Requests for Proposals” (RFPs) to generate purchase orders and contracts, respectively. RFQs are primarily used for the collection of retrospective samples from established banks while RFPs are used for the prospective collection of samples.

Institutions that contribute samples to TCGA are paid for their samples. In addition, the contributing institution has access to all of the molecular data generated on their samples, while maintaining a link between the TCGA unique identifier and their own unique identifier. This permits contributing institutions to link back to the clinical data for their samples and to enter into collaborations with other institutions that have similar data on TCGA samples, thus increasing the power of outcome analysis.

[edit] TCGA Funding

The NCI and NHGRI equally co-funded the Pilot Project with $50M for the first three years. The NCI has committed $25M/year of appropriated funds for five years for TCGA Phase II. The NHGRI has committed $25M/year of appropriated funds for two years. The beginning of the second phase of the project coincides with President Obama’s American Recovery and Reinvestment Act of 2009(ARRA), providing $153.5M of additional funding to the NCI beyond their appropriated funds. The Office of the Director of the NIH has provided another $25M of ARRA funds dedicated to sequence analysis and another $25M of ARRA funds in the second year of Phase II if substantial progress is made during year 1. In all, $150M will be spent on sequencing. Another $70M will be spent on tissue accrual, sample QC and biomolecule (DNA and RNA) isolation.

[edit] Organization of the Project

TCGA has a number of different types of centers that are funded to generate and analyze data. TCGA is the first large-scale genomics project funded by the NIH to include significant resources to bioinformatic discovery. The NCI has devoted 50% of TCGA appropriated funds, approximately $12M/year, to fund bioinformatic discovery. Genome Characterization Centers and Genome Sequencing Centers generate data. Two types of Genome Data Analysis Centers utilize the data for bioinformatic discovery. Two centers are funded to isolated biomolecules from patient samples and one center is funded to store the data. For more information on TCGA centers see http://cancergenome.nih.gov/wwd/program/.

Genome Characterization Centers (GCC): There are six GCCs funded by the NCI. These include the Broad Institute, Harvard, University of North Carolina, University of Southern California, Baylor College of Medicine and the British Colombia Cancer Center.

Genome Sequencing Centers (GSC): There are three GSCs co-funded by the NCI and NHGRI. These include the Broad Institute, Washington University and Baylor College of Medicine.

Genome Data Analysis Centers (GDAC): There are seven GCACs funced by the NCI. Three are called GDAC-As, which are responsible for the integration of data across all characterization and sequencing centers. The GDAC-As include The Broad Institute, University of North Carolina and the Lawrence Berkeley National Laboratory. Four centers are called GDAC-Bs, which are responsible for the biological interpretation of TCGA data. The GDAC-Bs include University of California at Santa Cruz, MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center and The Institute for Systems Biology. All seven GDACs work together to develop an analysis pipeline for automated data analysis.

Data Coordinating Center (DCC):

The Data Coordinating Center is the central repository for TCGA data. It is also responsible for the quality control of data entering the TCGA database. The DCC also maintains the TCGA Data Portal which is where users access TCGA data.

Biospecimen Core Resource (BCR):

There are currently two BCRs funded by the NCI; Nationwide Children’s Hospital and The International Genome Consortium. These two centers are responsible for verifying the quality and quantity of tissue shipped by tissue source sites, the isolation of DNA and RNA from the samples, quality control of these biomolecules and the shipment of samples to the GSCs and GCCs.

[edit] List of Tumors and Entrance of a Tumor Type into TCGA

A preliminary list of tumors for TCGA to study was generated by compiling incidence and survival statistics from the SEER Cancer Statistic website (http://seer.cancer.gov/). In addition, U.S. current “Standard of Care” was considered when choosing the top 25 tumor types, as TCGA is targeting tumor types where resection prior to adjunct therapy is the standard of care.

TCGA Targeted Tumors: Lung squamous cell carcinoma, Kidney Papillary Carcinoma, Breast ductal carcinoma, Non-Hodgkins Lymphoma (ex Diffuse large B-cell lymphoma, Renal cell carcinoma, Cervical Cancer (squamous), Colon adenocarcinoma, Stomach adenocarcinoma, Hepatocellular carcinoma, Astrocytoma, Head and neck (oral) squamous cell carcinoma, Thyroid follicular carcinoma, Bladder urothelial carcinoma - nonpapillary, Thyroid papillary carcinoma, Uterine Corpus (endometrial carcinoma), Bladder urothelia carcinoma - papillary, Pancreatic ductal adenocarcinoma, Acute Myeloid Leukemia, Prostate adenocarcinoma, Chronic Lymphocytic Leukemia, Lung Adenocarcinoma, Cutaneous melanoma, Breast lobular carcinoma, Multiple Myeloma and Diffuse large B-cell lymphoma

TCGA is accruing samples for all of these tumor types simultaneously. As samples become available, the tumor types with the most samples accrued will be entered into production. For more rare tumor types, tumor types where samples are difficult to accrue and for tumor types where TCGA cannot identify a source of high quality samples, these types of cancer will enter the “TCGA production pipeline” in the second year of the project. This will give the TCGA Program Office additional time to accrue sufficient samples for the project. If TCGA plans to characterized 20 tumor types in five years and there are 25 potential tumor types on the list, obviously, five types of cancer will not be studied unless additional funds are made available.

[edit] TCGA Groups Publish First Paper

TCGA recently published its first results on GBM in Nature [1]. These first results published on 91 tumor-normal matched pairs. It is interesting to note that the paper suggests that 587 biospecimens were collected for the study. The significant loss of samples, from 587 to 91, was due to the strict quality control placed on the specimens. These controls included the requirement for the tumor samples to contain at least 80% tumor nuclei and no more than 50% necrosis. Moreover, a secondary pathology assessment had to agree that the original diagnosis of GBM was an accurate diagnosis. A last batch of tumor-normal matched samples were excluded because the DNA or RNA collected was not of sufficient quality or quantity to be analyzed by all of the different platforms used in this study.

All of the data from the paper, as well as data that has been collected since the publication is publicly available at the Data Coordinating Center (DCC) for public access.^[4] Most of the TCGA data is completely open access. However there is a tier of data, data that has information that can identify a specific patient, that is protected. This Clinically Controlled-Access data can be accessed only by individuals that apply. Approval is granted on a case-by-case basis and requires the end-user to submit an application to the Data Access Committee (DAC). This Data Use Certification provides evidence that the end user is a bona fide researcher and is asking a legitimate scientific question that merits access to individual level data http://cancergenome.nih.gov/dataportal/data/access/.^{[citation needed]} This process is similar to that of other NIH-funded programs, including dbGAP.

[edit] See also

• Cancer Genome Project at the Wellcome Trust Sanger Institute

[edit] References

[edit] External links

• The Cancer Genome Atlas