Abstract
INTRODUCTION AND OBJECTIVE: Then landscape of genomic variations in unresectable Chinese prostate cancer (PCa) patients was unclear, which was essential in guiding drug therapy and prognosis predicting. We performed next generation sequencing (NGS) in unresectable PCa patients in order to study the somatic and germline variations in ctDNA, especially the prevalence and types of variations within two novel tumor suppressor genes PLXNA1 and PCDH9, and co-occurrence between PLXNA1 variations and the variations within other PCa-relevant pathways. METHODS: Targeted NGS was performed on ctDNA obtained from 243 unresectable Chinese PCa patients using a validated 90-PCa-relevant-gene panel. The whole coding sequence (cds) regions and partial intron regions of the 90-gene were sequenced. Co-occurrence analysis was performed using R software, version 3.6.1 (R Foundation for Statistical Computing) and maftools package. RESULTS: In 243 blood samples collected, 233 (95.9%) patients carried somatic or germline variations, and 112 (46.1%) patients have at least one mutation classified as pathogenic or likely pathogenic. There were 671 somatic and 308 germline mutations detected, with an average of 4.0 mutations per patient. The top frequent somatic mutation genes were AR (12.8%), TP53 (8.6%), KMT2C (4.5%), BRAF (2.3%) and CDK12 (2.3%). And the top frequent germline mutation genes were BRCA2 (9.1%), APC (4.9%), ATR (4.9%), ATM (4.5%) and BARD1 (4.1%), most of which belong to DNA damage repair pathway. Notably, 12 patients (4.9%) harbored PLXNA1 alterations and 1 patient (0.4%) harbored PCDH9 alterations. Among 14 PLXNA1 variations, 11 were single nucleotide variations and 3 were copy number gains, which occurred mainly in Sema domain and IPT/TIG domain. Furthermore, co-occurrence of variations within PLXNA1 and two genes (CCND1 and RB1) in cell cycle pathway was significant (p<0.05, Fisher Exact test). CONCLUSIONS: This study shows the landscape of both somatic and germline variations in unresectable Chinese PCa patients, which might be valuable to assess potential druggable markers and prognostic predictors. Source of Funding: None.
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