TY - JOUR
T1 - Genomic and epigenomic signatures in ovarian cancer associated with resensitization to platinum drugs
AU - Fang, Fang
AU - Cardenas, Horacio
AU - Huang, Hao
AU - Jiang, Guanglong
AU - Perkins, Susan M.
AU - Zhang, Chi
AU - Keer, Harold N.
AU - Liu, Yunlong
AU - Nephew, Kenneth P.
AU - Matei, Daniela
N1 - Funding Information:
We thank Dr. Doug Rusch, Aaron Buechlein, and Dave Miller (Center for Genomics and Bioinformatics, Indiana University, Indianapolis, IN) for help with data analysis and Dr. Pearlly Yan (The Ohio State University, Columbus, OH) for technical assistance. This work was funded by the National Cancer Institute Award CA182832-01 and the V- Foundation (to D. Matei and K.P. Nephew).
Funding Information:
We thank Dr. Doug Rusch, Aaron Buechlein, and Dave Miller (Center for Genomics and Bioinformatics, Indiana University, Indianapolis, IN) for help with data analysis and Dr. Pearlly Yan (The Ohio State University, Columbus, OH) for technical assistance. This work was funded by the National Cancer Institute Award CA182832-01 and the V-Foundation (to D. Matei and K.P. Nephew).
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethyla-tion450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1,659 genes differentially expressed in pretreatment versus posttreatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-193a, and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize ovarian cancer cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of ovarian cancer patients. Significance: Epigenomic targeting may improve therapeutic outcomes in platinum-resistant and recurrent ovarian cancer in part by effects on DNA repair and antitumor immune responses.
AB - DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethyla-tion450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1,659 genes differentially expressed in pretreatment versus posttreatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-193a, and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize ovarian cancer cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of ovarian cancer patients. Significance: Epigenomic targeting may improve therapeutic outcomes in platinum-resistant and recurrent ovarian cancer in part by effects on DNA repair and antitumor immune responses.
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UR - http://www.scopus.com/inward/citedby.url?scp=85041471047&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-1492
DO - 10.1158/0008-5472.CAN-17-1492
M3 - Article
C2 - 29229600
AN - SCOPUS:85041471047
SN - 0008-5472
VL - 78
SP - 631
EP - 644
JO - Cancer Research
JF - Cancer Research
IS - 3
ER -
