Plasma genetic and genomic abnormalities predict treatment response and clinical outcome in advanced prostate cancer
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Shu Xia1,2,*, Manish Kohli3,*, Meijun Du2, Rachel L. Dittmar2, Adam Lee4, Debashis Nandy3, Tiezheng Yuan2, Yongchen Guo2, Yuan Wang2, Michael R. Tschannen5, Elizabeth Worthey5, Howard Jacob5, William See6, Deepak Kilari6, Xuexia Wang7, Raymond L. Hovey8, Chiang-Ching Huang7 and Liang Wang2
1 Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
2 Department of Pathology and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
3 Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
4 Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
5 Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA
6 Department of Urology, Medical College of Wisconsin, Milwaukee, WI, USA
7 Joseph J. Zilber School of Public Health, University of Wisconsin, Milwaukee, WI, USA
8 Great Lakes Genomics Center, School of Freshwater Sciences, University of Wisconsin, Milwaukee, WI, USA
+ These authors have contributed equally to this work
Manish Kohli, email:
Liang Wang, email:
Keywords: prostate cancer, liquid biopsy, plasma, cell free DNA, next generation sequencing
Received: January 23, 2015 Accepted: March 20, 2015 Published: April 15, 2015
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.
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