MP45-13: Association Between Polymorphisms of Homologous Recombination RAD51B and Disease Recurrence in a Prospective Cohort of Prostate Cancer Patients Undergoing Radical Prostatectomy

Vito Cucchiara*, Luigi Nocera, Dejan Lazarevic, Davide Cittaro, Matteo Zoccolillo, Milan, Italy, Giorgio Gandaglia, Elio Mazzone, Armando Stabile, Francesco Barletta, Simone Scuderi, Daniele Robesti, Andrea Necchi, Milano, Italy, Vincenzo Mirone, Napoli, Italy, Pierre I. Karakiewicz, Montreal, Canada, Francesco Montorsi, Milano, Italy, Giovanni Tonon, Milan, Italy, Alberto Briganti, Milano, Italy

Introduction: Genetic polymorphisms in DNA repair genes may induce individual variations in DNA repair capacity, which may contribute to Prostate Cancer (PCa) development and aggressiveness. Homologous recombination repair genes (HRR), such as RAD51B, play a critical role in maintaining chromosomal integrity. We aimed at investigating the association between genetic variants in HRR genes and biochemical recurrence (BCR) in PCa patients following radical prostatectomy (RP).

Methods: After Ethical approval, we genotyped gDNA of 345 PCa patients with PCa treated with RP ± extended pelvic lymph node dissection (cases) and of 267 healthy individuals with no family history of PCa (controls). A total of 7 single nucleotide polymorphisms (SNPs) (rs7141529_RAD51B, rs117879878_PCA3, rs34764062_DLK2, rs1419133_PRUNE2, rs2227983_EGFR, rs5919432_AR, and rs6152_AR) were significantly more frequent in cases vs. controls (all p<0.001) with ORs ranging from 1.51 to 3.08 per risk allele. Gene enriched library was prepared using Fluidigm System and loaded on Illumina MiSeq platform. The prognostic role of the 7 variants were investigated in a validation cohort of 179 surgically treated PCa patients. The association between SNPs status and BCR was assessed in uni- and multivariable Cox regression analyses after adjustments for age, PSA, surgical margins, pT, pathological ISUP Grade Group and adjuvant therapies.

Results: Overall, the mono-allelic and bi-allelic expression of rs7141529 genotype C in RAD51B-gene were present in 45 (25%) and 30 (17 %) patients. Thirty men exhibited ISUP grade 4-5 and 48 men harbored pT3 disease, while 24 patients (13%) received adjuvant therapy. Among all patients, 47 patients (26%) experienced BCR during a median follow up of 54 months. At univariable analysis, bi-allelic expression of rs7141529 genotype C in RAD51B gene was associated with shorter BCR-free survival compared to genotype T. Multivariable analyses corroborated this finding. The bi-allelic expression of rs7141529 genotype C represented an independent predictor of BCR after adjusting for confounders (HR: 3.3, p=0.03). All other SNPs were not significantly associated with BCR (all p>0.3).

Conclusions: Polymorphic variants of genes involved in DNA repair, such as RAD51B, could modulate DNA repair capacity and thus have a great impact on cancer development and progression.  Using a comprehensive approach, we showed that the bi-allelic expression of rs7141529 genotype C in RAD51B-gene is a significant predictor of BCR. Further data are needed to validate these findings and to assess the role of rs7141529 polymorphism in the identification of PCa patients with poor prognosis.

Source of Funding: none