Mutational landscape and molecular signatures have recently been characterized in advanced prostate cancers and have suggested new insights in targetable pathways for disease management. Gene mutation and whole genome SNP analyses were performed on a cohort of 95 metastatic prostate patients in order to establish correlations between clinical profile, germline and somatic alterations in DNA repair pathway.
Next generation sequencing targeting coding regions of 111 candidate genes and 27,000 genome-wide single nucleotide polymorphisms was performed on DNA extracted from retrospective paraffin embedded tumoral tissues and blood (or saliva) of each patient. DNA repair deficiency in tumoral samples was assessed by establishing microsatellite instability status (MSI), somatic mutation load (SML) and homologous recombination deficiency (HRD) score.
Ancestry was European (White Caucasian), African (Black Afro Caribbean or west African) and Asian in 58.9%, 37.9% and 3.2% of cases, respectively. The median ages (ranges) at diagnosis and at metastatic diagnosis were 69 (45-92) and 70 (45-92), respectively. 97.9% of patients were M1 (79.3% presented bone metastases), and 2.1% were T4. Germline mutations were identified in 21.1% of patients (90% in genes from homologous recombination pathway). We found 4 (4.3%) positive MSI+ tumors, 3 of them resulted from a somatic mutation of the mismatch repair (MMR) gene MSH2. These tumors showed the highest tumor mutation burden (median SML = 31.31/Mb for MSI+ versus 15.58/Mb for MSI- tumors, P=0.0026) and were characterized by extensive loco-regional involvement without bone metastasis. 20.3% of the samples had a HRD score > 29. The frequency of HRD score >29 was higher among prostate cancer patients with a germline mutation than among patients without mutation (43.8% versus 13.8%, P=0.01). Indeed, 46.7% of patients with a HRD score >29 harbored a germline DNA repair gene mutation. The most frequent somatic mutations were observed in TP53 (31.6%), PTEN (7.4%), APC (6.3%), CTNNB1 (6.3%), CDK12 (5.2%), PRKDC (5.2%), MSH3 (5.2%), ATM (4.2%), MSH2 (4.2%) and POLE (4.2%). Notably, somatic alterations of CDK12 were always biallelic and were only found in patients with bone metastases.
Among this cohort of advanced prostate cancer patients, 5.2% with CDK12 somatic mutation and 21.1% with germline DNA repair gene mutation could be candidate to immunotherapy and PARP1 inhibition, respectively. HRD score > 29 could be used to identify patients with germline HR gene mutations. We found a subset of tumoral samples with high SML associated with microsatellite instability, mutation in the MMR gene MSH2, and a specific phenotype with locoregional extension and late metastatic process.