Analysis of the 10q11 Cancer Risk Locus Implicates MSMB and NCOA4 in Human Prostate Tumorigenesis

Abstract

Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states. Family history has long been recognized as an important risk factor for prostate cancer. Beginning in 2006, researchers have identified several genetic variants that are associated with prostate cancer risk. Intriguingly, the majority of prostate cancer risk variants do not reside in genes. Determining the genes involved in the development of disease, therefore, has proved challenging. In this study we interrogate a known prostate cancer risk polymorphism on chromosome 10—rs10993994. We report that this variant is significantly associated with the RNA expression levels of two genes—MSMB and NCOA4. When these expression changes are modeled in a cell line, prostate cells that were previously non-tumorigenic acquire a property known as anchorage independence, a characteristic of cancer cells. Notably, the prostate risk variant is not associated with expression or functional changes in breast or colon cells. In addition, the effects are most pronounced in normal rather than tumor prostate tissue. Overall, these findings help define the genes driving prostate cancer risk at chromosome 10. More generally, the discoveries demonstrate the importance of considering several target genes, as well as the importance of cellular context (tissue type and histological state), in future analyses of other genetic risk regions.