Impact of germline CHEK2 mutations on biochemical relapse free survival and metastasis free survival after radical treatment for patients with prostate cancer

Abstract

Objective : to evaluate the prognostic value of pathogenic germline BRCA1, BRCA2 and CHEK2 mutations on biochemical relapse-free survival (BRFS) and metastasis-free survival (MFS) following radical treatment in patients with localized and locally advanced prostate cancer (PCa). Materials and methods . Tumor features and outcomes of 102 patients with PCa were analyzed. In all patients nadir prostate-specific antigen (PSA) have been achieved: radical prostatectomy was undergone by 85 patients; 17 patients received radical radiotherapy. Exclusion criteria were postoperative nadir PSA >0.2 ng/mL, adjuvant hormone therapy. During follow-up a total of 65 (63.7 %) patients developed biochemical relapse (BCR), and 39 (38.2 %) patients developed metastatic progression of PCa. All patients were genotyped for clinically significant pathogenic germline mutations 1100delC, I157Tand IVS2+1G>A in the CHEK2gene, 185delAG, 4153delA, 5382insC, 3875del4, 3819del5, C61G, 2080delA in the BRCA1 gene, 6174delT in the BRCA2 gene by polymerase chain reaction real-time using a set “OncoGenetics” (LLC “Research and Production Company DNA-Technology”, Russia, registration certificate № 2010/08415). The second step was the determination of the coding part of the BRCA1 and BRCA2 genes by the Sanger sequencing using a set “Beckman Coulter enomeLab GeXP”. Results . Pathogenic germline mutations in the CHEK2 gene were identified in 16 (15.7 %) patients: heterozygous missense mutation I157T (c.470T>C, rs17879961) was identified in 15 (14.7 %) patients, heterozygous mutation IVS2+1G>A (c.319+1G>A, rs765080766) was identified in 1 (0.9 %) patient. No cases of the 1100delC mutation in the CHEK2 gene and clinically significant mutations in the BRCA1 and BRCA2 genes were detected. Germline mutations I157TandIVS2+1G>A in the CHEK2gene are statistically significant independent unfavorable prognostic factor for BRFS (hazard ratio (HR) 3.272; 95 % confidence interval (CI) 1.688—6.341, p <0.001) and marginally significant independent unfavorable prognostic factor for MFS (HR 2.186; 95 % CI 0.932—5.126, p = 0.072). Subgroup analysis confirm independent prognostic value of germline CHEK2 mutations in patients with localized PCa (for BRFS HR 3.048; 95 % CI 1.024—9.078; p = 0.045; for MFS HR 5.168; 95 % CI 1.231—21.699; p = 0,025), and its marginally significant prognostic value in patient with locally advanced PCa T3-T4N0M0 (for BRFS HR 3.099; 95 % CI 0.991-9.689; р = 0.052) and TanyN1M0 stage (for MFS HR 5.089; 95 % CI 0.724-35.755; p = 0.102). Germline mutations I157T and IVS2+1G>A in the CHEK2 gene are associated with increased risk of early BCR during 12 months (HR 3.795; 95 % CI 2.06-6.98; p <0.001) and early metastatic progression during 24 months (HR 6.72; 95 % CI 2.02-22.34; p = 0.004) following radical treatment. This study has certain limitations due to its retrospective recruitment and a small sample of patients. Conclusions . Our results confirm that germline CHEK2 mutations I157T and IVS2+1G>A are an unfavorable prognostic factor for patients with PCa, associated with increased risk of early biochemical relapse and metastatic progression, worse BRFS and MFS.