The Cancer Genome Atlas Research Network A Sight

Authors: Thomas J Giordano

Publish Date: 2014/11/01

Volume: 25, Issue: 4, Pages: 362-365

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Abstract

Starting in 2010 I’ve enjoyed the distinct privilege to be the disease cochair of the thyroid cancer project of The Cancer Genome Atlas TCGA This program is a joint effort of the National Cancer Institute NCI and the National Human Genome Research Institute NHGRI The program was conceived and proposed in 2005 see http//cancergenomenihgov/PublishedContent/Files/pdfs/TCGA executive summarypdf and initiated in 2006 with several pilot projects with the overarching goal being the comprehensive characterization of the somatic changes within the cancer genome After initiation of pilot projects on brain ovary and lung cancers 1 2 3 TCGA was substantially expanded with a large fund infusion from The American Recovery and Reinvestment Act of 2009 ARRA to include the most common types of cancers including thyroid cancer Here my ultimate goals are to describe the key elements of the consortium and to discuss its relevance for the surgical pathology community as we are in the early stages of a genomic transformationIt was pure serendipity that I with an introduction from Carolyn Compton was first to knock on the TCGA thyroid door Given my prior publications on gene expression profiles and genomic studies of thyroid cancer 4 5 6 TCGA leadership asked me if I would like to serve as the disease cochair I immediately accepted their offer as TCGA represented the exact type of genomic science that wanted to pursue My informatics cochair was Gad Getz of the Broad Institute of Harvard and MIT and the Department of Pathology of Massachusetts General Hospital It would become instantly obvious that Gaddy is a brilliant computational biologist formally trained in physics and then molecular biology The project officially launched in May 2010 and we would share a wild journey over the next 4 yearsThe first activity of TCGA projects is to form a Disease Working Group DWG a committee of disease experts whose primary mission is to determine the contents of the various data forms used to capture relevant clinicopathologic information With input from TCGA leadership we invited a group of accomplished endocrinologists thyroid surgeons and thyroid pathologists to join the DWG Once assembled by May 2010 the DWG was also charged with defining the scope of the project specifically deciding on which types of thyroid cancer to study TCGA strongly prefers to study one specific subtype of cancer in each project for ovary they selected papillary serous adenocarcinoma 2 The DWG initially proposed studying the full spectrum of follicular cellderived thyroid cancers from welldifferentiated carcinomas ie papillary and follicular to poorlydifferentiated and anaplastic/undifferentiated carcinomas However that idea was not acceptable to TCGA because this approach would likely dilute the statistical power needed to find new cancer genes Looking back there was a large degree of truth to that argument but it would have also been beneficial to study in parallel a small cohort of histologically aggressive forms of thyroids cancers to permit direct comparisons between the different thyroid cancer types Given that papillary thyroid carcinoma PTC is the most common type of thyroid cancer combined with the requirement for highquality frozen tissues selecting PTC for study was the only viable optionThe DWG of each project also guides with assistance from the Biospecimen Core Resource BCR see below the development of several forms to ensure standardized collection of pathology and clinical data The Initial Case Quality Control Form captures initial pathology information The Enrollment Form captures relevant clinical information and is only completed after the specimen passes key histologic and molecular metrics and is approved by the BCR for inclusion in the study The FollowUp Form captured outcome data and is only completed after 12 months has lapsed since case enrollment These forms can be found at the BRC website see http//wwwnationwidechildrensorg/biospecimencoreresourceclinicaldataformsstandardWhile the DWG was doing their work the Biosample Core Resource BCR began receiving PTC samples and matched normal blood nonneoplastic thyroid tissue from the contralateral lobe in cases with unifocal PTC was eventually permitted after it was determined to be essentially genetically indistinguishable from white blood cells from Tissue Source Sites TSSs along with the data detailed in the Case Quality Control Form Academic hospitals and commercial tissue banks served as TSSs with IRB approval The BCR for the thyroid project was located at The Research Institute at Nationwide Children’s Hospital in Columbus Ohio under the leadership of Julie GastierFoster see http//wwwnationwidechildrensorg/biospecimencoreresourceforthecancergenomeatlas The BCR was responsible for all aspects of tissue collection storage and handling as well as nucleic acid extractions and distribution throughout the network for data generation In addition the BCR checks and verifies the clinical data before being uploaded to the Data Coordinating Center DCCCases were diagnosed as PTC by the pathologists from the respective submitting institutions In addition as part of the quality control process the pathology was reviewed at the BCR with the assistance of several expert thyroid pathologists Despite these efforts the cohort is nonetheless still prone to the interobserver diagnostic variability that is well documented to occur in thyroid cancer especially the follicular variant of PTC 7 8 9The data generating capabilities of TCGA are extensive Three Genome Sequencing Centers GSCs were established Broad Institute Baylor College of Medicine and Washington University School of Medicine to perform largescale DNA sequencing using nextgeneration NGS sequencing technologies Numerous Genome Characterization Centers GCCs were established to perform a variety of molecular assays to characterize the cancer genome Each GCC had a special area of expertise including copy number alterations Broad and Harvard epigenomics Johns Hopkins and University of southern California mRNA expression University of North Carolina miRNA analysis British Columbia Cancer Agency targeted sequencing Baylor and functional proteomics MD Anderson Cancer CenterThe Data Coordinating Center DCC handled data management In the genomic age in which genomes can be used to identify individuals 10 data security is vitally important yet one of the primary goals of TCGA is to make the data freely available to the cancer research community Finding the correct balance between protecting patient’s confidentiality and providing access to the data was accomplished by developing policies in which different levels of data were made available with data use certification see http//cancergenomenihgov/abouttcga/policies/policiesguidelines TCGA also maintains a data portal for distribution of data see https//tcgadatancinihgov/tcga/ as well as funds the Cancer Genomics Hub for distribution of primary sequencing data see https//cghubucscedu

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