Hye Sook Chon

Moffitt Cancer Center, Tampa, Florida, United States

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Publications (21)84.36 Total impact

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    ABSTRACT: Cytoreductive surgery is the cornerstone of ovarian cancer (OVCA) treatment. Detractors of initial maximal surgical effort argue that aggressive tumor biology will dictate survival, not the surgical effort. We investigated the role of biology in achieving optimal cytoreduction in serous OVCA using microarray gene expression analysis. For the initial model, we used a gene expression signature from a microarray expression analysis of 124 women with serous OVCA, defining optimal cytoreduction as removal of all disease greater than 1 cm (with 64 women having optimal and 60 suboptimal cytoreduction). We then applied this model to 2 independent data sets: the Australian Ovarian Cancer Study (AOCS; 190 samples) and The Cancer Genome Atlas (TCGA; 468 samples). We performed a second analysis, defining optimal cytoreduction as removal of all disease to microscopic residual, using data from AOCS to create the gene signature and validating results in TCGA data set. Of the 12,718 genes included in the initial analysis, 58 predicted accuracy of cytoreductive surgery 69% of the time (P = 0.005). The performance of this classifier, measured by the area under the receiver operating characteristic curve, was 73%. When applied to TCGA and AOCS, accuracy was 56% (P = 0.16) and 62% (P = 0.01), respectively, with performance at 57% and 65%, respectively. In the second analysis, 220 genes predicted accuracy of cytoreductive surgery in the AOCS set 74% of the time, with performance of 73%. When these results were validated in TCGA set, accuracy was 57% (P = 0.31) and performance was at 62%. Gene expression data, used as a proxy of tumor biology, do not predict accurately nor consistently the ability to perform optimal cytoreductive surgery. Other factors, including surgical effort, may also explain part of the model. Additional studies integrating more biological and clinical data may improve the prediction model.
    International Journal of Gynecological Cancer 07/2015; 25(6):1000-1009. DOI:10.1097/IGC.0000000000000449 · 1.95 Impact Factor

  • Gynecologic Oncology 04/2015; 137:169. DOI:10.1016/j.ygyno.2015.01.424 · 3.77 Impact Factor

  • Gynecologic Oncology 04/2015; 137:145-146. DOI:10.1016/j.ygyno.2015.01.364 · 3.77 Impact Factor

  • Gynecologic Oncology 04/2015; 137:102. DOI:10.1016/j.ygyno.2015.01.253 · 3.77 Impact Factor

  • Gynecologic Oncology 06/2014; 133:138. DOI:10.1016/j.ygyno.2014.03.361 · 3.77 Impact Factor
  • Reem Abdallah · Hye Sook Chon · Jesus Gonzalez Bosquet ·
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    ABSTRACT: The objective of this study was to investigate the role of microarray gene expression analysis in predicting the feasibility of complete cytoreduction in ovarian cancer. Microarray expression of 507 women with ovarian cancer from The Cancer Genome Atlas was initially analyzed and a gene expression signature created. Complete cytoreduction was defined as removal of all tumors with no macroscopic residual disease. The model was applied to the Australian Ovarian Cancer Study data set with 216 ovarian cancer samples. One hundred fifteen women had complete cytoreduction in The Cancer Genome Atlas data set with significantly higher 5-year overall survival as compared with the 392 women with macroscopic residual disease (P<.001). A total of 12,718 genes were analyzed; 142 predicted accuracy of complete cytoreduction 69% of the time (P=.02). The model was more precise in predicting incomplete cytoreduction with macroscopic residual tumor with a sensitivity of 82% and a positive predictive value of 78%. The performance, measured by the area under the receiver operating characteristic curve was 63%. When applied to the Australian Ovarian Cancer Study set, with 58 women with complete cytoreduction and 158 with macroscopic residual, the accuracy was 72% (P<.019) and it was still more sensitive predicting incomplete cytoreduction with a sensitivity of 83% and a positive predictive value of 79%, and the area under the receiver operating characteristic curve was 68%. This analysis stresses again on the importance of complete cytoreductive surgery in ovarian cancer to microscopic disease and shows that gene expression analysis might have a role in predicting patients who are not amenable to complete cytoreduction and thus would have shorter survival.
    Obstetrics and Gynecology 05/2014; 123 Suppl 1:89S. DOI:10.1097/01.AOG.0000447422.93940.61 · 5.18 Impact Factor
  • Hye Sook Chon · Reem Abdallah · Jesus Gonzalez Bosquet ·
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    ABSTRACT: To investigate if gene expression can differentiate endometrial cancer risk classification based on GOG 99 study in The Cancer Genome Atlas patients. Gene expression was extracted from 271 endometrioid endometrial cancer samples in the TCGA database. Patients were stratified to high risk, high intermediate risk, and low or low intermediate risk based on clinicopathologic parameters from GOG 99. Genes differentially expressed between the classes at univariate significance level of less than .001 were included in the gene signature. There were 167 patients in the low-risk group, 81 patients in the high intermediate-risk group, and 23 patients in the high-risk group in The Cancer Genome Atlas database. GOG 99 risk classification and FIGO (International Federation of Gynecology and Obstetrics) stage were independently significant for survival in the multivariate analysis (P<.001). A total of 18,048 genes were included in the initial analysis. Four hundred forty-six genes classified high risk, high intermediate risk, and low or low intermediate risk subgroup individually (P=.01) with an accuracy of 58% and a κ coefficient of 0.32. When combining high-risk and high intermediate-risk groups, the gene signature compared with low-risk patients included 608 genes (P=.01) with an accuracy of 69% and a κ coefficient of 0.36 (area under the curve 0.69), closer to the values of the gene signature including only low-risk compared with high-risk patients (accuracy 81%, κ 0.33, area under the curve 0.74). Gene expression analysis could differentiate risk groups in endometrioid endometrial cancer. The gene signature grouping high intermediate risk and high risk compared with low risk seems to be more accurate than using all three risk groups. This gene signature may help to identify higher risk patients with endometrial cancer before surgery.
    Obstetrics and Gynecology 05/2014; 123 Suppl 1:90S. DOI:10.1097/01.AOG.0000447424.95726.84 · 5.18 Impact Factor
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    ABSTRACT: Paclitaxel is a mainstay of treatment for many solid tumors, and frequently, clinical outcome is influenced by paclitaxel sensitivity. Despite this, our understanding of the molecular basis of paclitaxel response is incomplete. Recently, it has been shown that microRNAs (miRNAs) influence messenger RNA (mRNA) transcriptional control and can contribute to human carcinogenesis. In the present study, our objective was to identify miRNAs associated with cancer cell line response to paclitaxel and to evaluate these miRNAs as therapeutic targets to increase paclitaxel sensitivity. We measured the expression of 335 unique miRNAs in 40 human cancer cell lines selected from the NCI panel. We then integrated miRNA expression data with publicly available paclitaxel-sensitivity (GI50) data for each of the 40 cell lines to identify miRNAs associated with paclitaxel sensitivity. Ovarian cancer cell lines with differential miRNA expression and paclitaxel sensitivity were transiently transfected with miRNA precursors and inhibitors, and the effects on in vitro cell paclitaxel sensitivity were evaluated. Pearson's correlation identified 2 miRNAs (miR-367 and miR-30a-5p) associated with the NCI40 cell line in vitro paclitaxel response (P<0.0003). Ovarian cancer cells were selected based on the association between paclitaxel sensitivity and miR-367/miR-30a-5p expression. Overexpression of miR-367 in the paclitaxel-sensitive cells [PA1; IC50, 1.69 nM, high miR-367 (2.997), low miR-30a-5p (-0.323)] further increased paclitaxel sensitivity, whereas miR-367 depletion decreased paclitaxel sensitivity. In contrast, overexpression and depletion of miR-30a-5p in the paclitaxel-resistant cells [OVCAR4; IC50, 17.8 nM, low miR-367 (-0.640), high miR-30a-5p (3.270)] decreased and increased paclitaxel sensitivity, respectively. We identified and successfully targeted miRNAs associated with human cancer cell line response to paclitaxel. Our strategy of integrating in vitro miRNA expression and drug sensitivity data may not only aid in the characterization of determinants of drug response but also in the identification of novel therapeutic targets to increase activity of existing therapeutics.
    Oncology Reports 11/2013; 31(1). DOI:10.3892/or.2013.2847 · 2.30 Impact Factor
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    ABSTRACT: To evaluate the biologic validity of ovarian cancer (OVCA) screening and early detection efforts and to characterize signaling pathways associated with human cancer metastasis and patient survival. Using genome-wide expression profiling and DNA sequencing, we compared pelvic and matched extra-pelvic implants from 30 patients with advanced-stage OVCA for expression of molecular signaling pathways and p53 gene mutations. Differentially expressed pathways were further evaluated in a series of primary or early-stage versus metastatic or recurrent cancer samples from 389 ovarian, prostate, and oral cancer patients. Metastasis pathways were also evaluated for associations with survival in nine independent clinico-genomic datasets from 1,691 ovarian, breast, colon, brain, and lung cancer and leukemia patients. The inhibitory effects of one pathway (TGF-WNT) on in-vitro OVCA cell migration were studied. Pelvic and extra-pelvic OVCA implants demonstrated similar patterns of signaling pathway expression and identical p53 mutations. However, we identified 3 molecular pathways/cellular processes that were differentially expressed between pelvic and extra-pelvic OVCA samples and between primary/early-stage and metastatic/advanced or recurrent ovarian, oral, and prostate cancers. Furthermore, their expression was associated with overall survival from ovarian cancer (P=0.006), colon cancer (1 pathway at P=0.005), and leukemia (P=0.05). Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration. Advanced-stage OVCA has a unifocal origin in the pelvis. Molecular pathways associated with extra-pelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease.
    American journal of obstetrics and gynecology 08/2013; 209(6). DOI:10.1016/j.ajog.2013.08.004 · 4.70 Impact Factor
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    ABSTRACT: AKT, a key regulator of diverse tumor signaling, is associated with progression of many cancers. Here, we investigated 1) the influence of AKT on survival from ovarian cancer (OVCA), 2) the activity of the AKT inhibitor perifosine +/- cisplatin, and 3) the molecular determinants of perifosine-response. Phospho-AKT expression values and Affymetrix U133a expression data were downloaded from The Cancer Genome Atlas. Pearson correlation was used to determine associations between overall survival from OVCA and therapy response. Genes and represented signaling pathways associated with perifosine-response were explored in OVCA cells (n=10) and the NCI60 cancer cell panel. Pathway expressions, modeled by PCA, were evaluated for influences on survival using publically available clinico-genomic datasets. Phospho-AKT (serine473) expression correlated with survival from OVCA (P<0.05) and platinum-response (P=0.004). In vitro, perifosine showed anti-proliferative effects against OVCA cells and potentiated cisplatin-induced growth arrest. Perifosine-response was associated with the expression (FDR<0.05) of 7 signaling pathways in OVCA cells and 64 signaling pathways in the NCI60 cell panel. Three pathways were found in common: 1) Cytoskeleton remodeling/Cytoskeleton remodeling (Cyto), 2) Cell adhesion/Chemokines and adhesion (Chemokines), and 3) Cytoskeleton remodeling/TGF-WNT (TGF-WNT). The TGF-WNT was associated with survival from OVCA (P=0.0055). AKT signaling is an important determinant of OVCA response to chemotherapy and overall patient survival. Our data provide insight into the molecular basis to perifosine activity and identifies pathways associated with perifosine sensitivity and patient clinical outcome.
    Gynecologic Oncology 07/2013; 131(1). DOI:10.1016/j.ygyno.2013.07.088 · 3.77 Impact Factor
  • H. Chon · A. Herschberger · J. Lee · R. Wenham ·

    Gynecologic Oncology 07/2013; 130(1):e32-e33. DOI:10.1016/j.ygyno.2013.04.137 · 3.77 Impact Factor
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    ABSTRACT: Most women with advanced-stage epithelial ovarian cancer (OVCA) ultimately develop chemoresistant recurrent disease. Therefore, a great need to develop new, more active, and less toxic agents and/or to optimize the efficacy of existing agents exists. In this study, we investigated the activity of Avemar, a natural, nontoxic, fermented wheat germ extract (FWGE), against a range of OVCA cell lines, both alone and in combination with cisplatin chemotherapy and delineated the molecular signaling pathways that underlie FWGE activity at a genome-wide level. We found that FWGE exhibited significant antiproliferative effects against 12 human OVCA cell lines and potentiated cisplatin-induced apoptosis. Pearson correlation of FWGE sensitivity and gene expression data identified 2142 genes (false discovery rate < 0.2) representing 27 biologic pathways (P < 0.05) to be significantly associated with FWGE sensitivity. A parallel analysis of genomic data for 59 human cancer cell lines matched to chemosensitivity data for 2,6-dimethoxy-p-benzoquinone, a proposed active component of FWGE, identified representation of 13 pathways common to both FWGE and 2,6-dimethoxy-p-benzoquinone sensitivity. Our findings confirm the value of FWGE as a natural product with anticancer properties that may also enhance the activity of existing therapeutic agents. Furthermore, our findings provide substantial insights into the molecular basis of FWGE's effect on human cancer cells. RESEARCH HIGHLIGHTS:
    International Journal of Gynecological Cancer 07/2012; 22(6):960-7. DOI:10.1097/IGC.0b013e318258509d · 1.95 Impact Factor
  • Hye Sook Chon · William D. Bush · Chang Won Kang · Mitchel Hoffman ·
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    ABSTRACT: In this report we describe transperitoneal robotic-assisted paraaortic lymphadenectomy via the right lateral decubitus position to treat solitary recurrence in a patient with cervical carcinoma. This is, to our knowledge, the first report utilizing the right lateral decubitus position rather than the traditional approach with the Trendelenberg position. This approach adds another option for surgical approaches to the paraaortic lymph nodes, particularly in subgroups of patients who have significant cardiopulmonary cormobidities and are unable to tolerate the steep Trendelenburg position.
    Journal of Robotic Surgery 06/2012; 7(2). DOI:10.1007/s11701-012-0350-7
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    ABSTRACT: Carboplatin and cisplatin, alone or in combination with paclitaxel, have similar efficacies against ovarian cancer (OVCA) yet exhibit different toxicity profiles. We characterised the common and unique cellular pathways that underlie OVCA response to these drugs and analyse whether they have a role in OVCA survival. Ovarian cancer cell lines (n=36) were treated with carboplatin, cisplatin, paclitaxel, or carboplatin-paclitaxel (CPTX). For each cell line, IC(50) levels were quantified and pre-treatment gene expression analyses were performed. Genes demonstrating expression/IC(50) correlations (measured by Pearson; P<0.01) were subjected to biological pathway analysis. An independent OVCA clinico-genomic data set (n=142) was evaluated for clinical features associated with represented pathways. Cell line sensitivity to carboplatin, cisplatin, paclitaxel, and CPTX was associated with the expression of 77, 68, 64, and 25 biological pathways (P<0.01), respectively. We found three common pathways when drug combinations were compared. Expression of one pathway ('Transcription/CREB pathway') was associated with OVCA overall survival. The identification of the Transcription/CREB pathway (associated with OVCA cell line platinum sensitivity and overall survival) could improve patient stratification for treatment with current therapies and the rational selection of future OVCA therapy agents targeted to these pathways.
    British Journal of Cancer 05/2012; 106(12):1967-75. DOI:10.1038/bjc.2012.207 · 4.84 Impact Factor
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    ABSTRACT: Ovarian cancer (OVCA) is the most lethal gynecological malignancy. The high mortality rate associated with this disease is due in large part to the development of resistance to chemotherapy; however, the biological basis of this remains unclear. Gemcitabine is frequently used for the treatment of patients with platinum-resistant OVCA. We report molecular signaling pathways associated with OVCA response to gemcitabine. Forty-one OVCA cell lines were subjected to gene expression analysis; in parallel, IC50 values for gemcitabine were quantified using CellTiter-Blue viability assays. Pearson's correlation coefficients were calculated for gene expression and gemcitabine IC50 values. The genes associated with gemcitabine sensitivity were subjected to pathway analysis. For the identified pathways, principal component analysis was used to derive pathway signatures and corresponding scores, which represent overall measures of pathway expression. Expression levels of the identified pathways were then evaluated in a series of clinico-genomic datasets from 142 patients with stage III/IV serous OVCA. We found that in vitro gemcitabine sensitivity was associated with expression of 131 genes (p<0.001). These genes include significant representation of three molecular signaling pathways (p<0.02): O-glycan biosynthesis, Role of Nek in cell cycle regulation and Antiviral actions of Interferons. In an external clinico-genomic OVCA dataset (n=142), expression of the O-glycan pathway was associated with overall survival, independent of surgical cytoreductive status, grade and age (p<0.001). Expression levels of Role of Nek in cell cycle regulation and Antiviral actions of Interferons were not associated with survival (p=0.31 and p=0.54, respectively). Collectively, expression of the O-glycan biosynthesis pathway, which modifies protein function via post-translational carbohydrate binding, is independently associated with overall survival from OVCA. Our findings shed light on the molecular basis of OVCA responsiveness to gemcitabine and also identify a signaling pathway that may influence patient survival.
    International Journal of Oncology 04/2012; 41(1):179-88. DOI:10.3892/ijo.2012.1451 · 3.03 Impact Factor

  • Gynecologic Oncology 03/2012; 125:S139. DOI:10.1016/j.ygyno.2011.12.341 · 3.77 Impact Factor
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    ABSTRACT: To identify pathways that influence endometrial cancer (EC) cell sensitivity to cisplatin and to characterize the BCL2 antagonist of cell death (BAD) pathway as a therapeutic target to increase cisplatin sensitivity. Eight EC cell lines (Ishikawa, MFE296, RL 95-2, AN3CA, KLE, MFE280, MFE319, HEC-1-A) were subjected to Affymetrix Human U133A GeneChip expression analysis of approximately 22,000 probe sets. In parallel, endometrial cell line sensitivity to cisplatin was quantified by MTS assay, and IC(50) values were calculated. Pearson's correlation test was used to identify genes associated with response to cisplatin. Genes associated with cisplatin responsiveness were subjected to pathway analysis. The BAD pathway was identified and subjected to targeted modulation, and the effect on cisplatin sensitivity was evaluated. Pearson's correlation analysis identified 1443 genes associated with cisplatin resistance (P<0.05), which included representation of the BAD-apoptosis pathway. Small interfering RNA (siRNA) knockdown of BAD pathway protein phosphatase PP2C expression was associated with increased phosphorylated BAD (serine-155) levels and a parallel increase in cisplatin resistance in Ishikawa (P=0.004) and HEC-1-A (P=0.02) cell lines. In contrast, siRNA knockdown of protein kinase A expression increased cisplatin sensitivity in the Ishikawa (P=0.02) cell line. The BAD pathway influences EC cell sensitivity to cisplatin, likely via modulation of the phosphorylation status of the BAD protein. The BAD pathway represents an appealing therapeutic target to increase EC cell sensitivity to cisplatin.
    Gynecologic Oncology 01/2012; 124(1):119-24. DOI:10.1016/j.ygyno.2011.09.020 · 3.77 Impact Factor
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    ABSTRACT: Despite initial sensitivity to chemotherapy, ovarian cancers (OVCA) often develop drug resistance, which limits patient survival. Using specimens and/or genomic data from 289 patients and a panel of cancer cell lines, we explored genome-wide expression changes that underlie the evolution of OVCA chemoresistance and characterized the BCL2 antagonist of cell death (BAD) apoptosis pathway as a determinant of chemosensitivity and patient survival. Serial OVCA cell cisplatin treatments were performed in parallel with measurements of genome-wide expression changes. Pathway analysis was carried out on genes associated with increasing cisplatin resistance (EC(50)). BAD-pathway expression and BAD protein phosphorylation were evaluated in patient samples and cell lines as determinants of chemosensitivity and/or clinical outcome and as therapeutic targets. Induced in vitro OVCA cisplatin resistance was associated with BAD-pathway expression (P < 0.001). In OVCA cell lines and primary specimens, BAD protein phosphorylation was associated with platinum resistance (n = 147, P < 0.0001) and also with overall patient survival (n = 134, P = 0.0007). Targeted modulation of BAD-phosphorylation levels influenced cisplatin sensitivity. A 47-gene BAD-pathway score was associated with in vitro phosphorylated BAD levels and with survival in 142 patients with advanced-stage (III/IV) serous OVCA. Integration of BAD-phosphorylation or BAD-pathway score with OVCA surgical cytoreductive status was significantly associated with overall survival by log-rank test (P = 0.004 and P < 0.0001, respectively). The BAD apoptosis pathway influences OVCA chemosensitivity and overall survival, likely via modulation of BAD phosphorylation. The pathway has clinical relevance as a biomarker of therapeutic response, patient survival, and as a promising therapeutic target.
    Clinical Cancer Research 08/2011; 17(19):6356-66. DOI:10.1158/1078-0432.CCR-11-0735 · 8.72 Impact Factor

  • Cancer Research 01/2011; 70(8 Supplement):1645-1645. DOI:10.1158/1538-7445.AM10-1645 · 9.33 Impact Factor
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    Hye Sook Chon · Johnathan M Lancaster ·
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    ABSTRACT: DNA microarray technology is a powerful genomic tool that has the potential to elucidate the relationship between clinical features of cancers and their underlying biological alterations. We performed a systemic search in PubMed and Medline databases for recently published articles. The search terms used included "genome-wide," "microarrays," "ovarian cancer," "prognosis, " "gene expression profiling, " "molecular marker, " and "molecular biomarker. " Genome-wide expression profiling using DNA microarray technology has enhanced our understanding of the genes that influence ovarian cancer development, histopathologic subtype, progression, response to therapy, and overall survival. Gene expression profiling has demonstrated its utility in ovarian cancer research. It is hoped that with technologic, statistical, and bioinformatic advances, the reliability and reproducibility of this technique will increase, spawning clinical applications that may enhance our understanding of the disease and our ability to care for patients in the future.
    Cancer control: journal of the Moffitt Cancer Center 01/2011; 18(1):8-15. · 3.50 Impact Factor