Copy number variations in urine cell free DNA as biomarkers in advanced prostate cancer.

Abstract

Genetic profiling of urine cell free DNA (cfDNA) has not been evaluated in advanced prostate cancer. We performed whole genome sequencing of urine cfDNAs to identify tumor-associated copy number variations in urine before and after initiating androgen deprivation therapy in HSPC stage and docetaxel chemotherapy in CRPC stage. A log2 ratio-based copy number analysis detected common genomic abnormalities in prostate cancer including AR amplification in 5/10 CRPC patients. Other abnormalities identified included TMPRSS2-ERG fusion, PTEN gene deletion, NOTCH1 locus amplification along with genomic amplifications at 8q24.3, 9q34.3, 11p15.5 and 14q11.2, and deletions at 4q35.2, 5q31.3, 7q36.3, 12q24.33, and 16p11.2. By comparing copy number between pre- and post-treatment, we found significant copy number changes in 34 genomic loci. To estimate the somatic tumor DNA fraction in urine cfDNAs, we developed a Urine Genomic Abnormality (UGA) score algorithm that summed the top ten most significant segments with copy number changes. The UGA scores correlated with tumor burden and the change in UGA score after stage-specific therapies reflected disease progression status and overall survival. The study demonstrates the potential clinical utility of urine cfDNAs in predicting treatment response and monitoring disease progression.

• Authors: Yun Xia, Chiang-Ching Huang, Rachel Dittmar, Meijun Du, Yuan Wang, Hongyan Liu, Niraj Shenoy, Liang Wang, Manish Kohli
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 24 Pg. 35818-35831 (Jun 14 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27127882 (Publication Type: Journal Article)

Chemical References

• Androgen Antagonists
• Antineoplastic Agents
• Biomarkers, Tumor
• Cell-Free Nucleic Acids
• DNA, Neoplasm
• NOTCH1 protein, human
• Receptor, Notch1
• Receptors, Androgen
• Taxoids
• Docetaxel
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Aged
• Androgen Antagonists (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (genetics, urine)
• Cell-Free Nucleic Acids (genetics, urine)
• Chromosome Aberrations (drug effects)
• DNA Copy Number Variations
• DNA, Neoplasm (genetics, urine)
• Docetaxel
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Outcome Assessment, Health Care (methods)
• PTEN Phosphohydrolase (genetics)
• Prostatic Neoplasms (drug therapy, genetics, urine)
• Receptor, Notch1 (genetics)
• Receptors, Androgen (genetics)
• Taxoids (therapeutic use)