부산대학교 도서관

Patients diagnosed with advanced prostate cancer starting long term ADT follow a highly variable clinical course. Treatment intensification improves outcome overall, but without biomarkers we overtreat some subgroups and we are unable to direct the most effective treatment strategy to others. I developed a protocol for biomarker discovery and evaluation, leveraging the STAMPEDE trial, in which donated clinical samples are associated with prospective clinical data. Genomic copy number alterations commonly occur in prostate cancer, however the clinical implication of copy number change in advanced HSPC is unknown. I generated low coverage WGS data from FFPE tissue from participants in the control group of STAMPEDE and copy number profiled 688 tumour regions from 300 participants to describe the association between the burden of copy number alteration and outcome. The burden of copy number alteration positively associated with radiologically-evident distant metastases at diagnosis (P value=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P value=0.003) and death (P value=0.045) for each unit increase, stabilising into more modest increases with higher burdens. This association between copy number burden and outcome was similar in each of the metastatic states. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1X10-6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC, occurred more frequently in cases with higher copy number alteration. Intra-patient burden of copy number alteration variance associated with increased risk of distant metastases (Kruskal-Wallis test P value=0.037). In conclusion, copy number alteration at diagnosis in advanced prostate cancer associates with increased risk of metastases and accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death.