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


Background and Overall Goals

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 was jointly supported by the Epidemiology and Genomics Research Program and the Division of Cancer Biology. GAME-ON's overall goal was to foster an intra-disciplinary and collaborative approach to the translation of promising research leads deriving from the initial wave of cancer genome-wide association studies (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 was to provide a rigorous knowledge base that would enable clinical translation and public health dissemination of cancer GWAS findings. Teams of epidemiologists, basic scientists, and clinicians accomplished this goal by 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 were five cooperative agreements (U19) funded through the GAME-ON initiative. Each U19 included three projects focusing on the genomic, functional, and epidemiologic follow-up of GWAS of breast, prostate, colon, lung and ovarian cancers. The 5-year funding awards with 2-year no-cost extensions that were granted for this project ended in 2017.

Funded Projects

Click the links below each of the following project names to view brief descriptions of each project, links to more detailed abstracts, key personnelExternal Web Site Policy lists, and links to study information in the NIH database of Genotypes and Phenotypes (dbGaPExternal Web Site Policy). To maximize the scientific benefit and impact of the GAME-ON program, funded investigators were obligated to agree to data sharing requirementsExternal Web Site Policy as outlined in the general NIH and NCI policies for sharing large data sets.

  • 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

    View abstractExternal Web Site Policy

    The CORECT project investigated and identified 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

    View abstractExternal Web Site Policy

    The DRIVE project systematically discovered and replicated additional common genetic variants associated with breast cancer, assessed their biological significance, and developed evidence-based assessments of the clinical validity of prediction algorithms using these variants, as well as investigated their suitability for translation into clinical practice.

    dbGaP Links:

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

    dbGaP Links:

  • 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 was not previously 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, provided 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 integrated 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 allowed the study of gene-environment interactions. The goal was to identify individuals at high risk for lung cancer for whom screening and early detection would be most beneficial.

    dbGaP Links:

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.

GAME-ON
Organizational Structure

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Each of the five projects contained six GAME-ON Working Groups that promoted scientific collaborations in specific areas across cancer types:

  • Analytic and Risk Modeling Working Group
  • Epidemiology and Clinical Working Group
  • Epigenetics Working Group

Ancillary Groups

  • 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 of the Lead Investigators of the five U19s established the policies and processes across the initiative. NCI has appointed an External Advisory Committee that provided advice on the overall initiative progress.

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Selected GAME-ON Publications

Since the Initiative's inception in 2010, GAME-ON investigators have published more than 400 scientific manuscripts.

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

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Research Tools and Other Research Resources

Investigators also developed analytic software and tools that can be used by the scientific community at large.

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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