Prostate cancer: Correlating the clinical phenotype to the genotype.

Abstract

376 Background: Prostate cancer (PC) is the most common malignant tumor for men in Israel. There are known inherited pathogenic variants (PVs) in DNA repair genes that are linked to PC. Risk factors for hereditary PC include aggressive PC, a family history of PC, and/or other malignancies such as breast and ovarian cancer or colorectal and uterine cancer. Our main goal is to understand the impact of inherited PVs on the clinical characteristics of PC. This is to enable early detection, prediction of the course of the disease and response to treatment. Methods: This is a multidisciplinary multicenter study including urology, oncology and genetics departments enrolls PC patients from all ethnicities and stages during their clinic visit. Blood is taken and a family cancer history questionnaire is completed. Germline DNA is processed using exome slice technology targeting the following genes: BRCA2, BRCA1, CHEK2, ATM, PALB2, MLH1, MSH2/EPCAM, MSH6, PMS2, HOXB13, TP53, NBN, ATR, BRIP1, FANCA, GEN1, RAD51C, RAD51D, ABRAXAS1, MRE11. These genes are analyzed for PVs according to the "ACMG/AMP interpreting sequence variant guidelines". Results are returned to the patient and the recruiting physician. Results: Among 440 enrolled patients, 219 have completed germline genotyping analysis with the remainder under evaluation. Of these 207 (94%) are non-PV carriers and 12 (6%) carry PVs (see table). PVs included BRCA1/BRCA2 (n=1), BRCA2 (n=3), CHEK2 (n=2), MSH2+CHEK2 (n=1) and single cases of the following genes: BRCA1, TP53, ATR, FANCA and ABRAXAS1. PV carriers had higher proportions of metastatic disease at diagnosis (p=0.0015) and ISUP grade 4-5 (p=0.006). There is a significant increase in BRCA PVs both in metastatic disease and the ISUP grade 4-5. Conclusions: Early detection and favorable tumor biology are associated with curative treatment options. Those diagnosed in late stages or with high-risk characteristics have fewer curative treatment options available. Germline PVs are significantly higher in patients with late-stage disease, aggressive behavior and familial risk. Knowledge of PVs status may inform surveillance strategies for early detection. There exists a challenge in discovering PV male carriers due to the lack of germline testing in this group. Lastly, we are continuing our analysis of the genetic data to determine its link to high risk, aggressive and familial PC. Clinical phenotype and genotype. TotalN (%) Non-PV carriersN (%) PV germline carriersN (%) p-value* PV BRCA*** carriersN (%) p-value* Genetic results 219 207 (94) 12 (6) 5 Age at diagnosis Median(1,3 quartile) 71 (65,76) 70(65,76) 75(68,80) ns** 76(72,80) ns** Stage at diagnosis local or N+ 192 (88) 185 (89) 7 (58) 2 (40) Metastatic 27 (12) 22 (11) 5 (41) 0.0015 3 (60) 0.0007 ISUP 1-3 137 (63) 134 (65) 3 (25) 1 (20) 4-5 82 (37) 73 (35) 9 (75) 0.006 4 (80) *p-values are provided using Chi-square. **ns, not significant. **Double mutation counted as one.