Synergistic Interaction of <i>HOXB13</i> and <i>CIP2A</i> Predisposes to Aggressive Prostate Cancer.

Abstract

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 <i>HOXB13</i> G84E high-risk prostate cancer susceptibility mutation with other genetic loci remain unknown. The purpose of this study was to examine the interplay of <i>HOXB13</i> rs138213197 (G84E) and <i>CIP2A</i> rs2278911 (R229Q) germline variants on prostate cancer risk. Genotyping was done in Finnish discovery cohort (<i>n</i> = 2,738) and validated in Swedish (<i>n</i> = 3,132) and independent Finnish (<i>n</i> = 1,155) prostate cancer cohorts. Expression pattern analysis was followed by functional studies in prostate cancer cell models. Interplay of <i>HOXB13</i> (G84E) and <i>CIP2A</i> (R229Q) variants results in highest observed inherited prostate cancer risk (OR, 21.1; <i>P</i> = 0.000024). In addition, this synergism indicates a significant association of <i>HOXB13</i> T and <i>CIP2A</i> T dual carriers with elevated risk for high Gleason score (OR, 2.3; <i>P</i> = 0.025) and worse prostate cancer-specific life expectancy (HR, 3.9; <i>P</i> = 0.048), and it is linked with high PSA at diagnosis (OR, 3.30; <i>P</i> = 0.028). Furthermore, combined high expression of <i>HOXB13-CIP2A</i> 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 <i>CIP2A</i> locus and revealed that <i>HOXB13</i> functionally promotes <i>CIP2A</i> transcription. The study is limited to retrospective Nordic cohorts. Simultaneous presence of <i>HOXB13</i> T and <i>CIP2A</i> 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 <i>CIP2A</i> gene and functionally promotes <i>CIP2A</i> transcription.