Mutational and molecular signatures that were characterized in advanced prostate cancers (PCa) suggested new insights in targetable pathways for disease management. To establish correlations between clinical profile, germline and somatic alterations, targeted next generation sequencing (NGS) was performed on a cohort of 153 metastatic PCa patients.
NGS targeting coding regions of 111 candidate genes and 27,000 genome-wide SNPs was performed on DNA extracted from paraffin embedded tumoral tissues and blood of each patient. DNA repair deficiency in tumors was assessed by establishing microsatellite instability status (MSI), tumor mutational burden (TMB) and myChoice (Myriad Genetics) homologous recombination deficiency (HRD) score.
The median ages at diagnosis and at metastatic diagnosis were 68.5 and 70, respectively. 76,5% of patients were M1 (70.6% presented bone metastases), and 23.5% were either N1 or T4. The 5 MSI positive tumors (4.0%) showed the highest TMB values (median TMB 19.03/Mb for MSI+ vs 1.27/Mb for MSI-, P=0.0002) and were characterized by extensive loco-regional involvement without bone metastasis. Mutations in TP53 were the most frequent somatic alterations (28.6%), and were associated with a higher risk of metastases in other sites than bone (P<0.0001). The 4 patients (3.2%) who harbored a biallelic mutation of CDK12 all had bone metastasis. An HRD score > 29 was observed in 19.4% of the tumors, was more frequent among patients with a germline mutation (36.4% vs 15.0%, P=0.035), and was associated with a higher risk of bone metastasis (P=0.034). Patients with a germline or somatic mutation of BRCA2 had a higher median HRD score (P=0.026), and were characterized by a higher risk of death by PCa (P=0.0085).
Among these patients with advanced PCa, we identified molecular alterations associated with different clinical profiles: MSI+ tumors associated with loco-regional involvement without bone metastasis, mutations of TP53 associated with a higher risk of metastases in other sites than bone, biallelic mutation of CDK12 and HRD score >29 associated with the presence of bone metastasis, and lastly, BRCA2 mutation associated with a higher risk of death by prostate cancer.
Clinical trial identification
Legal entity responsible for the study
Myriad Genetics, Inc.
D. Iliev: Full/Part-time employment: Myriad Genetics, Inc. D. Pruss: Full/Part-time employment: Myriad Genetics, Inc. K.M. Timms: Full/Part-time employment: Myriad Genetics, Inc. All other authors have declared no conflicts of interest.