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Plasma genetic and genomic abnormalities predict treatment response and clinical outcome in advanced prostate cancer. Oncotarget 2015 Jun 30;6(18):16411-21 PMID: 25915538 PMCID: PMC4599278

Pubmed ID

25915538

Abstract

Liquid biopsies, examinations of tumor components in body fluids, have shown promise for predicting clinical outcomes. To evaluate tumor-associated genomic and genetic variations in plasma cell-free DNA (cfDNA) and their associations with treatment response and overall survival, we applied whole genome and targeted sequencing to examine the plasma cfDNAs derived from 20 patients with advanced prostate cancer. Sequencing-based genomic abnormality analysis revealed locus-specific gains or losses that were common in prostate cancer, such as 8q gains, AR amplifications, PTEN losses and TMPRSS2-ERG fusions. To estimate tumor burden in cfDNA, we developed a Plasma Genomic Abnormality (PGA) score by summing the most significant copy number variations. Cox regression analysis showed that PGA scores were significantly associated with overall survival (p < 0.04). After androgen deprivation therapy or chemotherapy, targeted sequencing showed significant mutational profile changes in genes involved in androgen biosynthesis, AR activation, DNA repair, and chemotherapy resistance. These changes may reflect the dynamic evolution of heterozygous tumor populations in response to these treatments. These results strongly support the feasibility of using non-invasive liquid biopsies as potential tools to study biological mechanisms underlying therapy-specific resistance and to predict disease progression in advanced prostate cancer.

Author List

Xia S, Kohli M, Du M, Dittmar RL, Lee A, Nandy D, Yuan T, Guo Y, Wang Y, Tschannen MR, Worthey E, Jacob H, See W, Kilari D, Wang X, Hovey RL, Huang CC, Wang L

Authors

Deepak Kilari MD Assistant Professor in the Medicine department at Medical College of Wisconsin
William A. See MD Chair, Professor in the Urologic Surgery department at Medical College of Wisconsin
Liang Wang MD, PhD Professor in the Pathology department at Medical College of Wisconsin




Scopus

2-s2.0-84937898954   21 Citations

MESH terms used to index this publication - Major topics in bold

Aged
Aged, 80 and over
Androgen Antagonists
Base Sequence
Biopsy
DNA Copy Number Variations
DNA, Neoplasm
Gene Dosage
Gene Library
Genome, Human
Genome-Wide Association Study
Humans
Male
Middle Aged
PTEN Phosphohydrolase
Plasma
Prostate
Prostatic Neoplasms
Recombinant Fusion Proteins
Sequence Analysis, DNA
Serine Endopeptidases
Trans-Activators
Transcriptional Regulator ERG
Treatment Outcome
jenkins-FCD Prod-336 69ef4a6b262d135130251597d5d39873903802b5