GWAS: Toward a Comprehensive Understanding of Cancer Causation

Genome-wide association studies (GWAS) have proven to be a valuable tool for uncovering the heritable component of cancer etiology. Emerging technologies have enabled researchers to interrogate the entire genome with relative ease, allowing for the identification of hundreds of new and unexpected associations that relate regions of the genome to disease risk. Investigators are increasingly able to pinpoint the genetic variants through resequencing and fine mapping, and then to pursue in-depth research into the functional and biological mechanisms underpinning the inherited genetic variation. The findings may eventually inform clinical studies aimed at risk prediction, early detection, and preventive or therapeutic interventions, as well as epidemiologic and statistical studies into gene-gene and gene-environment interactions aimed at a more complete understanding of cancer causation and progression.

In a recent example of groundbreaking post-GWAS research, Meredith Yeager, Ph.D., Core Genotyping Facility (CGF), Stephen J. Chanock, M.D., Director of CGF and Chief of DCEG's Laboratory of Translational Genomics, and Dr. Hong Lou and Dr. Michael Dean from the Center for Cancer Research (CCR) led one of the first studies to uncover the mechanisms relating a common genetic variant to prostate cancer (Lou H., et al. Proceedings of the National Academy of Sciences 2009;106(19):7933–7938). The study used fine mapping analysis of prostate cancer cases and controls from the NCI Cancer Genetic Markers of Susceptibility (CGEMS) project to confirm two independent GWAS that identified an association between a single-nucleotide polymorphism (SNP), rs10993994, on chromosome 10q11.2 with prostate cancer risk. The SNP is located in a region that plays a role in the expression of the MSMB gene, which codes for a protein implicated as a potential biomarker for prostate cancer and which may act as a tumor suppressor.

In follow-up functional analyses, the investigators explored how the two variants of the SNP, found either as a thymine (T) allele or a cytosine (C) allele, influence MSMB expression. Compared to the T allele, the C allele was associated with greater MSMB expression (see Figure 1). Previous studies have shown that as prostate cancer develops from early to late stages, MSMB expression progressively decreases. The T allele also has been found to be more common in prostate cancer patients than in controls. Further analysis revealed that the transcription factor CREB—a protein that plays a role in initiating gene expression—binds strongly to the C allele but does not bind to the T allele. No other SNP within the MSMB region showed significant functional associations with the gene, though further study is needed to investigate this region more comprehensively.

In regard to these findings, Dr. Yeager stated, "We were fortunate that the SNP identified by the GWAS was the same variant that influences the expression of MSMB, which is also a good candidate gene for prostate cancer. It is likely that other regions of the genome related to prostate cancer through GWAS will require much more time and effort to elucidate. We believe our findings illustrate an approach to how post-GWAS studies may be conducted."

This study models some of the goals outlined in recent NCI and National Human Genome Research Institute (NHGRI)-sponsored workshops on the current status and future directions in GWAS, which generate huge amounts of data. With the advent of increased technological capabilities, GWAS findings have grown dramatically. There are now close to 400 new regions in the genome associated with more than 75 different diseases and traits, all of which can be further explored through follow-up studies. Investigators subsequently gathered to discuss how to best manage, analyze, and pursue the vast number of associations resulting from GWAS.

"Once a GWAS signal is conclusively established, the next steps forward may be long and arduous, and require a stepwise approach to localize the common and rare variants that may be lurking in these regions," explained Dr. Chanock, who co-led the workshop on sequencing and post-GWAS research.

Many newly identified regions do not readily point to genes with known functions, and they often arise in so called "gene deserts." Follow-up studies, including fine mapping, deep sequencing, and functional analysis, are critical for analyzing the contribution of identified regions to the risk of disease and investigating whether SNPs discovered by GWAS represent the functional genetic variant or simply tag the true variants, which may be located nearby in the same haplotype. Furthermore, growing evidence shows that SNPs are not the only variation playing a role in cancer etiology. For example, researchers are now investigating the role of copy number variants, which are stretches of genomic sequence that are deleted or duplicated in varying degrees. These also may influence gene expression.

To facilitate NCI's trans-divisional collaborations aimed at refining and interpreting GWAS findings, DCEG and CCR have formed the Human Genetics and Genomics Working Group, cochaired by Margaret A. Tucker, M.D., Director of the Human Genetics Program and Chief of the Genetic Epidemiology Branch; Dr. Curtis Harris, Laboratory of Human Carcinogenesis, CCR; and Dr. Mary Carrington, Laboratory of Experimental Immunology, CCR. The intent of the DCEG-CCR working group is to capitalize on new research opportunities derived from GWAS by promoting innovative studies that use cutting-edge genomic technologies to elucidate the genetic pathways of carcinogenesis that may be amenable to clinical intervention.

Dr. Tucker explained, "There is an increasing need for genetic and molecular epidemiologists to work closely with basic and clinical scientists in search of the biological consequences of genetic variants associated with cancer risk. The goal of our working group is to foster transdisciplinary projects by developing communication tools linking DCEG and CCR scientists, promoting collaborative research infrastructure and training programs, and encouraging outreach to extramural scientists and companies actively engaged in the development and application of genomic technologies."

In addition, the working group has recently established funding opportunities for collaborative studies involving DCEG and CCR investigators to follow up on validated genetic loci revealed by GWAS or by linkage analyses of cancer-prone families. DCEG and CCR jointly fund proposals up to $100,000 per year, awarded for a maximum of two years per project. All proposals are peer reviewed and ranked by members of the working group and the Steering Committee of the NCI Center of Excellence in Integrative Cancer Biology and Genomics. Each proposal is reviewed for scientific merit, innovation and novelty of the approach, feasibility, potential clinical and public health impact, and evidence of interdivisional collaboration. To date, three projects have been funded through this mechanism, with final approval by the scientific directors of DCEG and CCR.

Approval has also been received to establish a postdoctoral fellowship program that features joint research at DCEG and CCR. "By working with scientists across the intramural program, we hope to train the next generation of transdisciplinary scientists who will contribute novel insights into the genetic component of cancer. It seems likely that these insights will inform the development of new measures aimed at cancer prevention, detection, and treatment," stated Dr. Tucker.

—Cherie M. Vitartas, M.P.H.

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