Fragmentation landscape of cell-free DNA in patients with metastatic castration-resistant prostate cancer (mCRPC) by race.

Abstract

e17028 Background: Prostate cancer (PCA) is the most diagnosed cancer, more than 1.2 million new cases are diagnosed. PCA-related deaths exceed 350,000 annually, making it one of the leading causes of cancer-associated death in men worldwide. Black men have both a higher incidence and significantly higher mortality rates from PCa than any other race/ethnicity. In the United States, White men had lower percentages of distant (5%) and unknown stage (6%) prostate cancer. However, the 5-year relative survival for distant-stage prostate cancer was lowest among White men (29.1%). Previous genomic studies have found that White men have lower mutation rates of the androgen receptor gene, EGFR, MYC, FGFR 1 , and CTNNB 1 than Black men. Cell-free DNA (cfDNA) fragmentomic studies have shown that shorter fragments are more likely to contain somatic mutations due to the increased likelihood of DNA damage occurring at the breakpoints of the fragment. These findings suggest the association between cfDNA fragment size and race. However, knowledge of fragmentomics in mCRPC regarding race is limited. Methods: Blood samples were obtained from 31 patients with mCRPC before initiation of treatment. Patients were recruited from the Baylor St. Luke’s Medical Center in Houston, Texas. Samples were separated with density centrifugation, and plasma DNA was isolated. All NGS testing was performed using the commercially available platforms by Tempus, Inc (Chicago, IL). Sequencing data was aligned to the hg38 genome using BWA-mem (v0.7.17) followed by deduplication of the aligned BAM files with sambamba (v0.8.1). cfDNApro R package was used to determine the cfDNA fragment size. The Wilcoxon Rank-Sum test was conducted to compare the cfDNA fragment sizes between AA and White men. Results: Sequencing data from the patient who reported his race as an Asian was excluded. A total of thirty samples were included in the final model (Black:17, White:13). The average cfDNA fragment size median was 142.1 bp (range: 134.7–144.5 bp). The median of the average cfDNA fragment size in AA patients was 142.5 bp (range: 134.7–144.5 bp), and in White was 141.8 bp (range: 134.7–144.1 bp). There was no difference in the average cfDNA fragment size by race (Wilcoxon Rank Sum test p-value > 0.05). We observed a main peak at 162 bp (Black: 163, White: 159 bp) corresponding to a single nucleosome and a smaller peak at 323 bp (Black: 324, White: 322 bp) corresponding to two nucleosomes. The diversity of fragment sizes at the first coding exon of each gene will be reported. Conclusions: Our present study is the first analysis to compare fragmentation patterns between Black and White mCRPC patients. Further analysis will enhance our understanding of the fragmentomics of mCRPC in relation to race.