Transcriptome and interactome analyses identify theTP53interacting geneRCCD1as a candidate susceptibility gene at the 15p26.1 breast and ovarian cancer risk locus

Abstract

ABSTRACTCommon genetic variation in a region on chromosome 15q26 confers susceptibility to breast and ovarian cancer. The P53 interacting gene RCCD1 in this region is a candidate susceptibility gene for both cancers. In this study, a colocalization analysis of breast and ovarian cancer case-control genetic association studies in over 145,000 and 146,000 controls fine mapped the shared association in this region to 17 pleiotropic credible causal risk variants (Pbreast< 1.16 × 10−14andPovary< 7.50 × 10−7). These variants were strongly associated with the expression of RCCD1 in normal breast and ovarian tissues. Circular chromosome conformation capture (4C) analysis ofRCCD1in breast and ovarian cancer cells identified similar patterns ofcis-interaction and significant binding site enrichment for theBRCA2interacting geneEMSY(Padjusted= 9.24 × 10−6). The 4C analysis pinpointed a single 2kB RCCD1 cis-interaction that contained two of the 17 shared risk variants. RCCD1trans-interacting regions mapped to previously identified genome wide significant (P < 5 × 10−8) breast cancer risk loci (1p34.2 and 3p14.1) and to the pleiotropic breast-ovarian cancer risk locus at chromosome 9q34.2. Stable overexpression of RCCD1 in breast and ovarian cancer precursor cells identified 13 and 11 differentially expressed genes (DEGs) respectively associated with breast and ovarian cancer risk at genome-wide significance (PMAGMA< 2.6 × 10−6after Bonferroni correction). Eighty-two DEGs shared between breast and ovarian cancer were strongly enriched in TP53 (P = 9.9 × 10−4), Hippo (P = 2.51 × 10−3) and TNF signaling (P = 4.7 × 10−3) pathways.