Abstract 3409: Whole genome sequencing of liquid tumor biopsies (ctDNA) from men with metastatic castration resistant prostate cancer

Abstract

Abstract Background: Prostate cancer (PC) is the fifth most lethal male malignancy worldwide, as advanced metastatic castration resistant PC (mCRPC) remains incurable. Genomic biomarkers that can predict treatment response are urgently needed to facilitate personalized mCRPC treatment. Such biomarkers can be identified by whole genome sequencing (WGS) of tumor biopsies. Blood plasma can serve as a non-invasive liquid tumor biopsy as it contains cell free DNA (cfDNA), a subset of which in cancer patients is tumor-derived (circulating tumor DNA; ctDNA). The biomarker discovery potential of WGS of cfDNA in mCRPC remains largely undescribed, as most WGS studies to date have focused on tissue biopsies. Thus, we here aimed to characterize the genomic tumor landscape of mCRPC using WGS of cfDNA. Methods: We previously performed low-pass WGS (mean coverage: 0.5X) of cfDNA sampled prior to initiation of first-line mCRPC treatment from 143 mCRPC patients (mean ctDNA fraction: 0.15). From these, 10 patients with high (>0.35) ctDNA fractions who received enzalutamide as first-line mCRPC treatment were selected for deeper WGS here. Matched germline DNA from buffy coat (peripheral blood mononuclear cells) was also sequenced. Single-nucleotide variants (SNVs) were called with Mutect2 and CaVEMan, indels with Mutect2 and Pindel, copy-number variants (CNVs) with ASCAT, and structural variants (SVs) with BRASS. For the final analysis, we considered only SNVs and indels called by both tools. Results: We sequenced germline samples to a mean coverage of 25X (range: 19-28X) and cfDNA samples to a mean coverage of 32X (range: 23-43X). We identified a median of 5,241 SNVs/indels (range: 3,422-48,314) per patient and the mean tumor mutation burden was 1.7 mutations/Mb. One sample had >9 times more SNVs/indels than the median, suggesting microsatellite instability. Among the most recurrently mutated genes were LRP1B (7/10 patients), ARSB (5/10 patients), and TP53 (4/10 patients). COSMIC mutational signature analysis revealed that the clock-like signatures 1, 5, and 40 were most frequent. In contrast, the hypermutated sample was driven primarily by the defective DNA mismatch repair signatures 15, 26, and 44. CNVs affected a mean of 40.9% of the genome. Common PC CNVs were observed, including gains at chromosome 8 (MYC) in 8/10 patients and losses at chromosome 10 (PTEN) in 5/10 patients. Recurrent focal amplifications (defined as >8 copies in regions <3 Mb) affected chromosome 15q11.2 in 3/10 patients, chromosome 22q11.21 in 3/10 patients, and chromosome Xq12, where AR is located, in 3/10 patients. Finally, we identified a median of 241 SVs (range: 92-525) per patient. SVs affecting TMPRSS2 were observed in 3/10 patients. Conclusion: This study highlights that WGS of cfDNA contributes to the identification of genomic aberrations that may serve as potential biomarkers to guide personalized treatment of mCRPC in the future. Citation Format: Simone Weiss, Philippe Lamy, Maibritt Nørgaard, Michael Knudsen, Jørgen B. Jensen, Jakob S. Pedersen, Michael Borre, Karina D. Sørensen. Whole genome sequencing of liquid tumor biopsies (ctDNA) from men with metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3409.