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Lynda Chin, M.D.
Professor of Dermatology, Harvard Medical School
Scientific Director, Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Co-leader, Melanoma Disease Program, Dana-Farber/Harvard Cancer Center
Principle Investigator, The Cancer Genome Atlas (TCGA)

Approximately 60 percent of patients diagnosed with cancer present as early stage disease (Stage I and II). Despite the favorable prognosis associated with treatment intervention of such early stage disease (typically surgical excision), there are a small, but significant, fraction of these cancers that appear to be hardwired for aggressive metastatic behavior and ultimately lethal outcome. The ability to stratify early-stage cancer patients into high- and low-risk groups based on the likelihood of metastasis and treat each group with appropriate treatment paradigms based on the underlying genetics of the tumor is a critical unmet goal of personalized cancer care. Needed is an in-depth understanding of the complex tumor biology encoded in the cancer genome and translation of such knowledge into evidence-based biomarkers capable of predicting the risk of metastasis and enlistment of aggressive cancers into tailored treatment strategies.

Our understanding and approach to cancer is evolving beyond a morphological based discipline to one viewed through a molecular lens. Building on the foundation of the human genome, a current major aim of cancer research is focused on the underlying genetic and epigenetic events governing the hallmarks of cancer with the goal of linking genotype with phenotype. Such an ambitious effort requires an integrated multi-disciplinary program across the entire cancer research enterprise that embraces genomics, proteomics, bioinformatics, nanotechnology, biospecimen science, model systems, amongst others. Cancer may be a disease of the genome, but cracking its deepest mysteries will requires more than generation of an 'atlas' - a systems biology solution is essential.

Removing the Blinders

Each individual tumor is the phenotypic consequence of aberrant genes and their complex interactions with the germline, tumor microenvironment and host context. Our failure to conquer cancer rests partly on the lack of a comprehensive view of the many levels of genome dysregulation - an approach to date akin to the 'blind men and elephant'. To gain needed visibility, a first step has been the initiation of efforts to gain a comprehensive atlas of the somatic alterations in the cancer genome and epigenome, along with resident germline profiles. This effort is embodied in The Cancer Genome Atlas (TCGA), a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), and the International Cancer Genome Consortium (ICGC), efforts that are systematically exploring the entire spectrum of acquired events associated with diverse human cancers.

The success of the TCGA pilot project has led to an expansion in scope in its new phase in which 20 tumor types will be characterized within the next five years. Whole-genome sequencing allows the complete characterization of genomic alterations, from point mutations to deletions and rearrangements. This methodology provides unprecedented resolution and accuracy while illuminating the complexity of the genome. Filtering the genomic noise will certainly benefit from comparative oncogenomics using genetically engineered mouse models of cancer, an approach that has been shown to be powerful in enabling culling of passenger mutations from drivers as well as identification of gene regulatory elements.

TCGA and other similar efforts to catalog the array of changes in the cancer genome is setting the stage for the development of more molecular-targeted interventions and prognostic biomarkers. But to achieve this promise requires an understanding of the functional consequences that derive from these genetic alterations. Proteomics can facilitate this process by applying newly developed methods and advanced analytical tools for the investigation of the protein complement, and offers our best hope of translating genetic knowledge into effective clinical tests and treatments that can improve patient outcomes.

A Protein Compass for the Cancer Genome Atlas

As cancer complexity is unraveled at the genomic and proteomic levels, data access, sharing and integration on common information platforms will become increasingly vital to maximize our understanding of cancer and create a global and integrated profile of the disease. Coordinated efforts linking NCI's TCGA and CPTC programs hold great promise in leading to greater data integration and more biological understanding for improved cancer care.

In a few short years, the CPTC program has accelerated the development, improvement and standardization of proteomic technologies for the detection of cancer-relevant proteins in clinical biospecimens. In the fall of 2009, leaders and experts from the extramural community, including myself and representatives from academic, private industry, and regulatory agencies, were convened by the NCI at a workshop entitled, "Implementation of a New Cancer Biomarker Development Pipeline," to discuss how best to optimize the output from the pilot phase of CPTC. Attendees agreed that one of the best strategy for CPTC Phase II involves a close collaboration with TCGA, because; the biological characterization and subsequent collection of matched genomic and proteomic data, combined with patient data, is going to provide a thorough assessment of disease, furthering our understanding of cancer at the molecular level.

We are entering a new era of cancer research, where the integration of critical fields - genomics and proteomics - and new technology promises to transform our ability to interrogate the genome. This new era holds the promise to enable prevention, facilitate early detection, and guide evidence-based interventions.