<p>Supplementary Figure S17 provides whole exome somatic mutation profiles in patients that did not show temporal changes in 72-gene panel mutation profiles</p>
<p>Supplementary Figure S19 shows the complete switch of circulating tumor DNA profile in patient 026 between baseline and first progression timepoints</p>
<p>Supplementary Figure S10 provides Kaplan-Meier plots showing duration of treatment response in patients with different baseline circulating tumor DNA fractions</p>
<p>Supplementary Figure S16 shows patients without evidence for somatic mutation profile change after treatment progression based on 72-gene targeted sequencing</p>
<p>Supplementary Figure S17 provides whole exome somatic mutation profiles in patients that did not show temporal changes in 72-gene panel mutation profiles</p>
<div>AbstractPurpose:<p>DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features.</p>Experimental Design:<p>We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically.</p>Results:<p><i>BRCA2, ATM</i>, and <i>CDK12</i> were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele–specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous <i>BRCA2</i> deletions. Tumor suppressors <i>TP53, RB1</i>, and <i>PTEN</i> were controlled via disruptive chromosomal rearrangements in <i>BRCA2-</i>defective samples, but via oncogene amplification in context of <i>CDK12</i> defects. <i>TP53</i> mutations were rare in cases with <i>ATM</i> defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of <i>BRCA2</i> and <i>CDK12</i>, but not <i>ATM</i>, was associated with poor clinical outcomes.</p>Conclusions:<p><i>BRCA2, ATM</i>, and <i>CDK12</i> defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.</p></div>
<div>AbstractPurpose:<p>DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features.</p>Experimental Design:<p>We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically.</p>Results:<p><i>BRCA2, ATM</i>, and <i>CDK12</i> were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele–specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous <i>BRCA2</i> deletions. Tumor suppressors <i>TP53, RB1</i>, and <i>PTEN</i> were controlled via disruptive chromosomal rearrangements in <i>BRCA2-</i>defective samples, but via oncogene amplification in context of <i>CDK12</i> defects. <i>TP53</i> mutations were rare in cases with <i>ATM</i> defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of <i>BRCA2</i> and <i>CDK12</i>, but not <i>ATM</i>, was associated with poor clinical outcomes.</p>Conclusions:<p><i>BRCA2, ATM</i>, and <i>CDK12</i> defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.</p></div>
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