Plasma genetic and genomic abnormalities predict treatment response and clinical outcome in advanced prostate cancer.
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.
Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Department of Pathology and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Shu
S
Xia
Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
Manish
M
Kohli
Department of Pathology and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Meijun
M
Du
Department of Pathology and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Rachel L
RL
Dittmar
Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
Adam
A
Lee
Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
Debashis
D
Nandy
Department of Pathology and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Tiezheng
T
Yuan
Department of Pathology and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Yongchen
Y
Guo
Department of Pathology and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Yuan
Y
Wang
Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Michael R
MR
Tschannen
Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Elizabeth
E
Worthey
Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Howard
H
Jacob
Department of Urology, Medical College of Wisconsin, Milwaukee, WI, USA.
William
W
See
Department of Urology, Medical College of Wisconsin, Milwaukee, WI, USA.
Deepak
D
Kilari
Joseph J. Zilber School of Public Health, University of Wisconsin, Milwaukee, WI, USA.
Xuexia
X
Wang
Great Lakes Genomics Center, School of Freshwater Sciences, University of Wisconsin, Milwaukee, WI, USA.
Raymond L
RL
Hovey
Joseph J. Zilber School of Public Health, University of Wisconsin, Milwaukee, WI, USA.
Chiang-Ching
CC
Huang
Department of Pathology and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Liang
L
Wang
D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use; D001483:Base Sequence; D001706:Biopsy; D056915:DNA Copy Number Variations / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics*; D015723:Gene Library; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000097:blood / Q000235:genetics; D010949:Plasma / Q000737:chemistry*; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000097:blood* / Q000235:genetics* / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000235:genetics; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000097:blood / Q000235:genetics; D015534:Trans-Activators / Q000097:blood / Q000235:genetics; D000071230:Transcriptional Regulator ERG; D016896:Treatment Outcome
D000726:Androgen Antagonists; D004273:DNA, Neoplasm; C072312:ERG protein, human; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human
cell free DNA; liquid biopsy; next generation sequencing; plasma; prostate cancer