Genetic Associations and Mechanisms in Oncology (GAME-ON): A Network of Consortia for Post-Genome Wide Association (Post-GWA) Research

Background and Overall Goals

Genome-wide association studies (GWAS) involve rapidly scanning markers across the complete genomes of a large number of cases and controls to find common genetic variations associated with a particular disease. Since 2005, such studies have identified a large number of loci with common genetic variants associated with cancer risk. However, the variants identified by these studies are usually markers and not the causal variants themselves. In addition, the biological mechanisms through which the associated loci confer cancer risk are often unknown. Lastly, the modulating effect of environmental and lifestyle factors need to be taken into account when estimating the risk conferred by the causal variants.

The Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative was launched by NCI in 2010 in response to RFA-CA-09-002External Web Site Policy, and it is jointly supported by the Epidemiology and Genomics Research Program and the Division of Cancer Biology. GAME-ON's overall goal is to foster an intra-disciplinary and collaborative approach to the translation of promising research leads deriving from the initial wave of cancer GWAS.

Figure: Phases of the post-GWAS research continuum, an illustration showing the spectrum of post-GWAS study types: 'pooled analyses,' 'replication,' 'fine mapping,' 'functional studies,' and finally 'epidemiology.' Arrows from narrowest focus (pooled analyses) to broadest (epidemiology) indicate that studies build on the knowledge gained from the preceding studies in the continuum.

Phases of the Post-GWAS
Research Continuum

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The long-term goal of the GAME-ON initiative is to provide a rigorous knowledge base that will enable clinical translation and public health dissemination of the GWAS findings. This goal is being achieved by teams of epidemiologists, basic scientists, and clinicians, collaborating on follow-up investigations of genomic regions that have been implicated in susceptibility to certain cancer types. The post-GWAS continuum of research addressed by this network of consortia includes:

  • Replication of previous findings and identification of new susceptibility loci through pooled or meta analyses and extension of GWAS to diverse populations
  • Fine mapping of identified loci to better pinpoint causal variants
  • Unraveling the function of identified genetic variants through functional and animal models studies
  • Examining the effect of gene-gene and gene-environment interplay in modulating the risk of disease, and
  • Using the knowledge acquired from these studies to develop risk prediction mechanisms that can be used by the general population and in clinics.

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Funded Projects, Working Groups, and Organizational Structure

Figure: Each awarded U19 encompasses three related projects focusing on the three areas of the post-GWAS continuum and requiring multi-disciplinary integration: 'discovery, expansion, and replication,' 'biological studies,' and 'epidemiologic studies.' A cycle of continuous knowledge integration is suggesting by arrows connecting the three project areas to each other.

Three Areas of the
Post-GWAS Continuum

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There are currently five cooperative agreements (U19) funded through the GAME-ON initiative. Each U19 includes three projects focusing on the genomic, functional, and epidemiologic follow-up of GWAS of breast, prostate, colon, lung and ovarian cancers.

Funded Projects

Click the links below each of the following project names to view brief descriptions of each project, links to more detailed abstracts, and key personnel lists.

  • ColoRectal Transdisciplinary Study (CORECT)
    Learn more about the CORECT study
    Contact PI: Stephen Gruber, M.D., Ph.D., M.P.H., University of Southern California

    The CORECT project is investigating and identifying susceptibility loci for colorectal cancer in order to characterize the biologic basis of inherited susceptibility and recognize how genetic variation may be quantified and modified by genetic and environmental risk factors. Complex models that take advantage of this new genetic information, together with known environmental factors for colorectal cancer, will expedite the translation of these findings into clinical practice.

  • Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE)
    Learn more about the DRIVE study

    Contact PI: David Hunter, M.B.B.S., Sc.D., Harvard University School of Public Health

    The DRIVE project is systematically discovering and replicating additional common genetic variants associated with breast cancer, assessing their biological significance, and developing evidence-based assessments of the clinical validity of prediction algorithms using these variants, as well as investigating their suitability for translation into clinical practice.

  • Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE)
    Learn more about the ELLIPSE study

    Contact PI: Christopher Haiman, Sc.D., University of Southern California

    View abstractExternal Web Site Policy
    ELLIPSE Key Personnel

    The ELLIPSE project is pursuing thorough identification and characterization of genomic loci associated with prostate cancer. The overarching goal is to discover the pathways that drive prostate cancer pathogenesis and to assess their role in clinical decision making.

  • Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)
    Learn more about the FOCI study

    Contact PI: Thomas Sellers, Ph.D., M.P.H., H. Lee Moffitt Cancer Center & Research Institute

    View abstractExternal Web Site Policy
    FOCI Key Personnel

    GWAS have successfully identified many common susceptibility alleles for multiple disease phenotypes, including the identification of genes involved in pathways not previously implicated in cancer. This has not been possible for ovarian cancer, but the recent completion of several independent GWAS, with the potential for replication in participating Ovarian Cancer Association ConsortiumExternal Web Site Policy (OCAC) sites, provides the opportunity to identify such alleles and match the success for other cancers.

  • Transdisciplinary Research in Cancer of the Lung (TRICL)
    Learn more about the TRICL study

    Contact PI: Christopher Amos, Ph.D., Dartmouth College

    View abstractExternal Web Site Policy
    TRICL Key Personnel

    The TRICL project is integrating data from eight GWAS studies on lung cancer to increase power to detect genetic factors influencing all types of lung cancer and to be able to analyze specific subsets, such as cases with early onset, specific histological sets, gender-defined groups, and never smokers. The extended sample size will allow study of gene-environment interactions. The goal is to identify individuals at high risk for lung cancer for whom screening and early detection would be most beneficial.

Working Groups and Organizational Structure

Figure: GAME-ON organizational structure. Six working groups operate across all five of the funded projects. Additionally, an advisory committee, steering committee, and executive committee oversee the activities of the working groups and projects.

Organizational Structure

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There are six GAME-ON Working Groups that cut across all five projects that promote scientific collaborations in specific areas across cancer types:

  • Analytic and Risk Modeling Working Group
  • Epidemiology and Clinical Working Group
  • Epigenetics Working Group
  • Functional Assays Working Group
  • Next Generation Genomics Technologies Working Group
  • TERT-CLPTM1L Working Group

Learn more about the GAME-ON Working Groups.

An Executive Committee composed by the Lead Investigators of the five U19s establishes the policies and processes across the initiative. NCI has appointed an External Advisory Committee to provide advice on the overall initiative progress.

The GAME-ON organizational structure allows for vertical and horizontal dissemination of knowledge and expertise.

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Participating Consortia

The GAME-ON initiative is one of the many ways in which EGRP works to facilitate collaborative research through a network of cancer epidemiology consortia. To maximize the scientific benefit and impact of the GAME-ON program, funded investigators must agree to data sharing requirementsExternal Web Site Policy as outlined in the general NIH and NCI policies for sharing large data sets. For questions related to GAME-ON data sharing, contact Stefanie Nelson, Ph.D..

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Since the Initiative's inception in 2010, GAME-ON investigators have published more than 150 scientific manuscripts.

View a list of GAME-ON publications and publication acknowledgement guidelines.

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Research Tools and Other Research Resources

Investigators are also developing analytic software and tools that can be used by the scientific community at large. The GAME-ON Initiative maintains a list of related research resources that may be valuable to investigators interested in post-GWAS research.

Learn more about tools created by GAME-ON investigators and other research resources.

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NCI Contacts

For questions related to the GAME-ON grant awards:

For OncoArray questions:

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