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Synergistic Interaction of HOXB13 and CIP2A Predisposes to Aggressive Prostate Cancer

Purpose: Distinguishing aggressive prostate cancer from indolent disease improves personalized treatment. Although only few genetic variants are known to predispose to aggressive prostate cancer, synergistic interactions of HOXB13 G84E high-risk prostate cancer susceptibility mutation with other genetic loci remain unknown. The purpose of this study was to examine the interplay of HOXB13 rs138213197 (G84E) and CIP2A rs2278911 (R229Q) germline variants on prostate cancer risk. Experimental Design: Genotyping was done in Finnish discovery cohort (n = 2,738) and validated in Swedish (n = 3,132) and independent Finnish (n = 1,155) prostate cancer cohorts. Expression pattern analysis was followed by functional studies in prostate cancer cell models. Results: Interplay of HOXB13 (G84E) and CIP2A (R229Q) variants results in highest observed inherited prostate cancer risk (OR, 21.1; P = 0.000024). In addition, this synergism indicates a significant association of HOXB13 T and CIP2A T dual carriers with elevated risk for high Gleason score (OR, 2.3; P = 0.025) and worse prostate cancer–specific life expectancy (HR, 3.9; P = 0.048), and it is linked with high PSA at diagnosis (OR, 3.30; P = 0.028). Furthermore, combined high expression of HOXB13-CIP2A correlates with earlier biochemical recurrence. Finally, functional experiments showed that ectopic expression of variants stimulates prostate cancer cell growth and migration. In addition, we observed strong chromatin binding of HOXB13 at CIP2A locus and revealed that HOXB13 functionally promotes CIP2A transcription. The study is limited to retrospective Nordic cohorts. Conclusions: Simultaneous presence of HOXB13 T and CIP2A T alleles confers for high prostate cancer risk and aggressiveness of disease, earlier biochemical relapse, and lower disease-specific life expectancy. HOXB13 protein binds to CIP2A gene and functionally promotes CIP2A transcription.