Comparative analysis of genomic alterations across castration-sensitive and castration-resistant prostate cancer via circulating tumor DNA sequencing.

BackgroundTo explore the genomic profiles of Chinese patients with castration-sensitive prostate cancer(CSPC) and those with metastatic castration-resistant prostate cancer(mCRPC) via germline and circulating tumor DNA(ctDNA) sequencing.MethodsA hybridization capture-based next-generation sequencing assay was used to identify germline and somatic alterations in 50 genes, including androgen receptor(AR) pathway genes, DNA damage repair(DDR) pathway genes, , and .ResultsWe successfully sequenced DNA from 396 blood samples and 32 matched tumor tissue samples from 396 patients. We observed a similar frequency of deleterious germline alterations between patients with CSPC and mCRPC(8.9%.9.8%, p>0.05). There was a high consistency(90.9%) between metastatic tumor tissue and matched ctDNA. Among ctDNA-positive patients, we observed significantly higher alteration frequencies of (27.2%.6.4%, p<0.001) and (36.8%.15.3%, p<0.001) in our mCRPC cohort compared with the SU2C-PCF cohort. Alteration frequencies of DDR pathway genes(66.7%.41.5%, p=0.015) and AR pathway genes(71.9%.48.8%, p=0.018) in patients with mCRPC were higher than in patients with metastatic CSPC(mCSPC). AR alteration was selectively enriched in mCRPC.ConclusionsThrough genomic profiling of prostate cancer across clinical states, we identified a similar frequency of deleterious germline alterations between patients with CSPC and mCRPC. We explored the genomic diversity of AR and DDR pathway genes between patients with mCSPC and mCRPC. Higher alteration frequencies of and were observed in our mCRPC cohort than in the SU2C-PCF cohort. Our findings support the view that ctDNA sequencing could guide clinical treatment for metastatic prostate cancer.