Translational Research Fulfilling the Promise of Genome-Wide Association Studies

In 2005, DCEG launched its first genome-wide association study (GWAS) as part of the NCI Cancer Genetic Markers of Susceptibility (CGEMS) initiative with the hope of uncovering novel genetic variations within the human genome that convey measurable cancer risk or protection among the general population. These variations would serve as leads for future research to identify the unique biologic mechanisms underlying the associations, thereby unifying epidemiologic, basic, and clinical scientists in a new area of multi-disciplinary translational research. The success of GWAS in producing these leads resulted in the establishment of DCEG’s Laboratory of Translational Genomics (LTG), which has led several follow-up studies since its inception in 2007.

Findings from LTG have confirmed that the promises of GWAS are being realized. Recently, Ludmila Prokunina-Olsson, Ph.D., a tenure-track investigator in LTG, and her team examined a single nucleotide polymorphism (SNP) in the PSCA gene that had been identified earlier in DCEG’s GWAS of bladder cancer. The PSCA protein is commonly expressed on the surface of tumor cells of different cancer types and is currently being tested as a potential drug target for treatments of prostate and pancreatic cancers. Dr. Prokunina-Olsson and her colleagues at LTG, NCI’s Center for Cancer Research, and other institutions used 278 bladder tumor samples collected from patients from DCEG’s New England Bladder Cancer Study and found the risk allele to be the strongest factor predicting surface expression of PSCA in bladder tumors, clearly separating these tumors into PSCA positive and negative (see Figure 1).

“This is an exciting finding,” Dr. Prokunina-Olsson said, “that suggests that specific therapies targeting PSCA could be effective in bladder cancer patients, and testing patients for the risk allele could be an important tool of precision medicine to predict treatment success.” Based on the frequency of this genetic variant, the anti-PSCA treatment might be beneficial to as many as 75 percent of all bladder patients. This work, "Genetic variant as a selection marker for anti-prostate stem cell antigen immunotherapy of bladder cancer", was published online in the Journal of the National Cancer Institute in December 2012.

DCEG’s translational efforts resulted in other exciting news when Dr. Prokunina-Olsson and Thomas O’Brien, M.D., M.P.H., a senior investigator in the Infections and Immunoepidemiology Branch (IIB), published work in Nature Genetics in January 2013 on a follow-up study of recent GWAS findings implicating SNPs near the IFNL3 gene as playing a role in the clearance of the hepatitis C virus (HCV), either spontaneously or in response to treatment. Chronic infection of HCV is a common cause of liver cancer, and identifying mechanisms responsible for HCV clearance is important in the clinical management of the disease, which is difficult to treat. Because of the challenges in linking the newly discovered variants to the likely candidate genes, Drs. Prokunina-Olsson and O’Brien conducted RNA sequencing in purified human liver cells treated in vitro to mimic HCV infection, which provided the investigators with a complete view of all genes expressed in the region of interest. Their work resulted in the discovery of a previously unknown gene in the interferon family, interferon lambda 4 (IFNL4).

Interferons are known to have broad effects in innate immunity that are important in infectious diseases and cancer. Remarkably, the existence of IFNL4 protein is found to be under complete genetic control: A deletion of one nucleotide within the first exon causes a frameshift and creates the IFNL4 protein, whereas the other allele does not create this interferon. The presence of the deletion allele and the IFNL4 protein results in poorer HCV clearance (see Figure 2).

The deletion allele is also more common among populations of African descent, which potentially explains why African-American patients have poorer response to current HCV treatments compared with individuals from other populations. “Not only does this finding add to our understanding of human immune response to viral infection,” Dr. O’Brien said, “but we’ve also identified a potential new clinical marker that predicts treatment outcomes better than the test currently in use.” The finding also opens the door to the development of new potential treatments for HCV. Drs. Prokunina-Olsson and O’Brien are now working with colleagues in and outside of NIH to evaluate the role of the IFNL4 gene in relation to other diseases and the response to IFN-alpha–based treatment of HCV and melanoma.