Circulating tumour DNA reveals genetic traits of patients with intraductal carcinoma of the prostate

Abstract

To investigate the genetic alterations of patients with prostate cancer (PCa) with and without intraductal carcinoma of the prostate (IDC-P). Patients and MethodsWe performed targeted sequencing of plasma cell-free DNA on 161 patients with prostate adenocarcinoma (PAC) with IDC-P and 84 without IDC-P. Genomic alterations were compared between these two groups. The association between genetic alterations and patients' survival outcomes was also explored. ResultsWe identified that 29.8% (48/161) and 21.4% (18/84) of patients with and without IDC-P harboured genomic alterations in DNA repair pathways, respectively (P = 0.210). Pathogenic germline DNA repair alterations were frequently detected in IDC-P carriers compared to IDC-P non-carriers (11.8% [19/161] vs 2.4% [two of 84], P = 0.024). Germline BReast CAncer type 2 susceptibility protein (BRCA2) and somatic cyclin-dependent kinase 12 (CDK12) defects were specifically identified in IDC-P carriers relative to PAC (BRCA2: 8.7% [14/161] vs 0% and CDK12: 6.8% [11/161] vs 1.2% [one of 84]). Patients with IDC-P had a distinct androgen receptor (AR) pathway alteration, characterised by an enrichment of nuclear receptor corepressor 2 (NCOR2) mutations compared with patients with pure PAC (21.1% [34/161] vs 6.0% [five of 84], P = 0.004). Increased AR alterations were detected in patients harbouring tumours with an IDC-P proportion of ≥10% vs those with an IDC-P proportion of <10% (6.4% [five of 78] vs 18.1% [15/83], P = 0.045). For IDC-P carriers, tumour protein p53 (TP53) mutation was associated with shorter castration-resistant-free survival (median 10.9 vs 28.9 months, P = 0.026), and BRCA2 alteration was related to rapid prostate-specific antigen progression for those receiving abiraterone treatment (median 9.1 vs 11.9 months, P = 0.036). ConclusionOur findings provide genomic evidence explaining the aggressive phenotype of tumours with IDC-P, highlighting the potential therapeutic strategies for this patient population.

Genomic Features and Clinical Implications of Intraductal Carcinoma of the Prostate

“…More than one-third (35.6%) of IDC-P-positive cases had alterations of DNA repair pathways in the CRPC cohorts, and this finding was approximately 10% higher than the results from previous studies [ 20 ]. More interestingly, pathogenic germline mutations in DNA repair genes, including BRCA2 and CDK12 , were more frequently detected in patients with IDC-P than in those without IDC-P. For instance, the prevalence of germline BRCA2 mutations was significantly higher in patients with IDC-P than in those with adenocarcinoma of the prostate (8.7% vs. 0%, respectively) [ 20 ]. For IDC-P carriers at CRPC status, patients with BRCA2 mutation showed shorter PSA-PFS after first-line abiraterone acetate administration (median 9.1 versus 11.9 months).…”

“…Exome sequencing data from The Cancer Genome Atlas (TCGA) showed that patients with IDC-P components had higher rates of point mutations in FOXA1 (15% vs. 5%), TP53 (19% vs. 10%), and SPOP (19% vs. 10%) than in those without IDC-P [ 32 ]. In addition, IDC-P carriers had a unique AR pathway aberration, such as enrichment of NCOR2 mutation, compared with individuals with pure prostate adenocarcinoma [ 20 ].…”

“…More interestingly, deleterious germline DNA repair gene mutations, including BRCA2, ATM, CHEK2, and BRCA1 , were detected in 40% of patients ( n = 10/25) with IDC-P compared with only 9% ( n = 11/125) of those without IDC-P [ 23 ]. Zhao et al [ 20 ] performed a targeted sequencing of circulating cell-free DNA obtained from 164 IDC-P carriers and 84 IDC-P noncarriers of prostate adenocarcinoma. They found that nearly one-third of patients with metastatic prostate cancer with IDC-P histology had DNA repair defects [ 20 ].…”

“…Zhao et al [ 20 ] performed a targeted sequencing of circulating cell-free DNA obtained from 164 IDC-P carriers and 84 IDC-P noncarriers of prostate adenocarcinoma. They found that nearly one-third of patients with metastatic prostate cancer with IDC-P histology had DNA repair defects [ 20 ]. More than one-third (35.6%) of IDC-P-positive cases had alterations of DNA repair pathways in the CRPC cohorts, and this finding was approximately 10% higher than the results from previous studies [ 20 ].…”

“…They found that nearly one-third of patients with metastatic prostate cancer with IDC-P histology had DNA repair defects [ 20 ]. More than one-third (35.6%) of IDC-P-positive cases had alterations of DNA repair pathways in the CRPC cohorts, and this finding was approximately 10% higher than the results from previous studies [ 20 ]. More interestingly, pathogenic germline mutations in DNA repair genes, including BRCA2 and CDK12 , were more frequently detected in patients with IDC-P than in those without IDC-P. For instance, the prevalence of germline BRCA2 mutations was significantly higher in patients with IDC-P than in those with adenocarcinoma of the prostate (8.7% vs. 0%, respectively) [ 20 ].…”