Convergent Genomics Validates C2orf43 Role in Prostate Cancer. B. B. Currall1,2, K. E. Wong1, N. G. Robertson1, A. Lunardi2,3, M. Reschke2,3, P. P. Pandolfi2,3, C. C. Morton1,2,4 1) Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Womens Hospital, Boston, MA 02115, USA; 2) Harvard Medical School, Boston, MA 20115; 3) Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; 4) Department of Pathology, Brigham and Womens Hospital, Boston, MA 02115, USA.

   Genome-wide association studies (GWAS) have implicated thousands of genes in multiple disease states, but it is often difficult to assess the impact of any given GWAS hit. Several recent GWAS and linkage studies have associated the SNP, rs13385191, with prostate cancer (PCa). Moreover, this SNP is suggested to be a cis-acting expressed quantitative locus (eQTL), which down-regulates the expression of a poorly annotated gene known as C2orf43. These data parallel findings in a human subject, enrolled in the Developmental Genome Anatomy Project (DGAP, www.dgap.harvard.edu) and referred to as DGAP056, who has a chromosomal translocation that disrupts C2orf43, resulting in decreased expression of this gene, and who developed early-onset PCa (age 38). Analysis of RNA expression in human primary and metastatic tumors, from the Memorial Sloan Kettering Cancer Center (MSKCC) prostate repository, shows that C2orf43 is one of the most frequently down-regulated genes in PCa and is even further reduced in metastatic prostate tumors as compared to primary prostate tumors. Importantly, C2orf43 knockout (KO) mice show both more severe and an increased rate (>3-fold) of prostate tumors than their wild-type (WT) littermates, substantiating that C2orf43 down-regulation is causative for prostate tumorigenesis. Accompanied with recent findings that C2orf43 is involved in intracellular cholesterol ester (iCE) metabolism and that elevated iCE is a common finding in PCa, these convergent data suggest that C2orf43 is central to a relatively unknown PCa pathway. This type of convergent genomic analysis demonstrates a useful and successful approach for both prioritization and validation of the pathological consequences of GWAS hits and helps further characterize their underlying biology.

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