Susan K Murphy

Publications (84) View all

• Article: Utilization of genomic signatures to identify high efficacy candidate drugs for chemo-refractory endometrial cancers.

  Budiman Kharma, Tsukasa Baba, Masaki Mandai, Noriomi Matsumura, Susan K Murphy, Hyun Sook Kang, Koji Yamanoi, Junzo Hamanishi, Ken Yamaguchi, Yumiko Yoshioka, Ikuo Konishi
  [show abstract] [hide abstract]
  ABSTRACT: Objectives: Endometrial cancer, one of the most common gynecologic malignancies, is increasing in Japan, nearly doubling over the last decade. High grade disease patients are often resistant to conventional chemotherapy with platinum agents; therefore discovery of efficacious new drugs in this setting is required to benefit chemo-refractory cases. Methods: The 50% Growth-Inhibitory (GI50) concentration of 27 clinically relevant drugs was measured in the NCI60 panel of cell lines. Gene expression data were analyzed using Bayesian binary regression, to first generate a response signature for each drug, then to calculate individual susceptibility scores using in vivo endometrial cancer data (GSE2109; http://www.ncbi.nlm.nih.gov/geo) and in vitro data (GSE25458), as well as to identify candidate drugs for chemo-refractory cases. Using these candidates, cell proliferation, apoptosis, and caspase assays were performed in vitro. The tumor growth-inhibitory effect of the candidate was also assessed in vivo using nude mice. Results: Through microarray analysis, Fludarabine and Temsirolimus showed higher susceptibility scores in high grade cases compared with cisplatin, doxorubicin, and paclitaxel. Fludarabine significantly inhibited cell proliferation and increased apoptosis in the cisplatin-resistant endometrial cancer cell line, HEC1A, relative to HEC50B (p<0.001). Fludarabine treatment also enhanced Caspase 3/7 activity in HEC1A relative to HEC50B cells (p<0.001), and inhibited the growth of HEC1A xenograft tumors relative to cisplatin (p<0.05). Conclusions: These results support that identification and use of genomic signatures can lead to identification of new therapeutic candidates that may prove beneficial to chemo-resistant cases. Fludarabine may be useful in targeting high grade, chemo-refractory endometrial cancer. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 04/2013; · 5.44 Impact Factor
• Article: Stress: A Possible Link between Genetics, Epigenetics, and Childhood Asthma.

  Susan K Murphy, John W Hollingsworth
  American Journal of Respiratory and Critical Care Medicine 03/2013; 187(6):563-4. · 11.08 Impact Factor
• Article: Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort.

  Adelheid Soubry, Joellen M Schildkraut, Amy Murtha, Frances Wang, Zhiqing Huang, Autumn Bernal, Joanne Kurtzberg, Randy L Jirtle, Susan K Murphy, Cathrine Hoyo
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND: Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene. METHODS: We examined DNA from umbilical cord blood leukocytes from 79 newborns, born between July 2005 and November 2006 at Duke University Hospital, Durham, NC. Their mothers participated in the Newborn Epigenetics Study (NEST) during pregnancy. Parental characteristics were obtained via standardized questionnaires and medical records. DNA methylation patterns at two DMRs were analyzed by bisulfite pyrosequencing; one DMR upstream of IGF2 (IGF2 DMR), and one DMR upstream of the neighboring H19 gene (H19 DMR). Multiple regression models were used to determine potential associations between the offspring's DNA methylation patterns and parental obesity before conception. Obesity was defined as body mass index (BMI) [greater than or equal to]30 kg/m2. RESULTS: Hypomethylation at the IGF2 DMR was associated with paternal obesity. Even after adjusting for several maternal and newborn characteristics, we observed a persistent inverse association between DNA methylation in the offspring and paternal obesity (beta-coefficient was -5.28, P = 0.003). At the H19 DMR, no significant associations were detected between methylation patterns and paternal obesity. Our data suggest an increase in DNA methylation at the IGF2 and H19 DMRs among newborns from obese mothers, but a larger study is warranted to further explore the potential effects of maternal obesity or lifestyle on the offspring's epigenome. CONCLUSIONS: While our small sample size is limited, our data indicate a preconceptional impact of paternal obesity on the reprogramming of imprint marks during spermatogenesis. Given the biological importance of imprinting fidelity, our study provides evidence for transgenerational effects of paternal obesity that may influence the offspring's future health status. See related commentary article here http://www.biomedcentral.com/1741-7015/11/30.
  BMC Medicine 02/2013; 11(1):29. · 6.03 Impact Factor
• Article: Associations between Methylation of Paternally Expressed Gene 3 (PEG3), Cervical Intraepithelial Neoplasia and Invasive Cervical Cancer.

  Monica D Nye, Cathrine Hoyo, Zhiqing Huang, Adriana C Vidal, Frances Wang, Francine Overcash, Jennifer S Smith, Brandi Vasquez, Brenda Hernandez, Britta Swai, Olola Oneko, Pendo Mlay, Joseph Obure, Marilie D Gammon, John A Bartlett, Susan K Murphy
  [show abstract] [hide abstract]
  ABSTRACT: Cytology-based screening for invasive cervical cancer (ICC) lacks sensitivity and specificity to discriminate between cervical intraepithelial neoplasia (CIN) likely to persist or progress from cases likely to resolve. Genome-wide approaches have been used to identify DNA methylation marks associated with CIN persistence or progression. However, associations between DNA methylation marks and CIN or ICC remain weak and inconsistent. Between 2008-2009, we conducted a hospital-based, case-control study among 213 Tanzania women with CIN 1/2/3 or ICC. We collected questionnaire data, biopsies, peripheral blood, cervical scrapes, Human papillomavirus (HPV) and HIV-1 infection status. We assessed PEG3 methylation status by bisulfite pyrosequencing. Multinomial logistic regression was used to estimate odds ratios (OR) and confidence intervals (CI 95%) for associations between PEG3 methylation status and CIN or ICC. After adjusting for age, gravidity, hormonal contraceptive use and HPV infection, a 5% increase in PEG3 DNA methylation was associated with increased risk for ICC (OR = 1.6; 95% CI 1.2-2.1). HPV infection was associated with a higher risk of CIN1-3 (OR = 15.7; 95% CI 5.7-48.6) and ICC (OR = 29.5, 95% CI 6.3-38.4). Infection with high risk HPV was correlated with mean PEG3 differentially methylated regions (DMRs) methylation (r = 0.34 p<0.0001), while the correlation with low risk HPV infection was weaker (r = 0.16 p = 0.047). Although small sample size limits inference, these data support that PEG3 methylation status has potential as a molecular target for inclusion in CIN screening to improve prediction of progression. IMPACT STATEMENT: We present the first evidence that aberrant methylation of the PEG3 DMR is an important co-factor in the development of Invasive cervical carcinoma (ICC), especially among women infected with high risk HPV. Our results show that a five percent increase in DNA methylation of PEG3 is associated with a 1.6-fold increase ICC risk. Suggesting PEG3 methylation status may be useful as a molecular marker for CIN screening to improve prediction of cases likely to progress.
  PLoS ONE 01/2013; 8(2):e56325. · 4.09 Impact Factor
• Article: Validation of ovarian cancer gene expression signatures for survival and subtype in formalin fixed paraffin embedded tissues.

  Gregory P Sfakianos, Edwin S Iversen, Regina Whitaker, Liudmila Akushevich, Joellen M Schildkraut, Susan K Murphy, Jeffrey R Marks, Andrew Berchuck
  [show abstract] [hide abstract]
  ABSTRACT: INTRODUCTION: Gene expression signatures have been identified for epithelial ovarian cancer survival (TCGA) and intrinsic subtypes (Tothill et al.). One obstacle to clinical translation is these signatures were developed using frozen tissue, whereas usually only formalin-fixed, paraffin embedded (FFPE) tissue is available. The aim of this study was to determine if gene expression signatures can be translated to fixed archival tissues. METHODS: RNA extracted from FFPE sections from 240 primary ovarian cancers were analyzed by DASL on Illumina BeadChip arrays. Concordance of expression at the individual gene level was assessed by comparing array data from the same cancers (30 frozen samples analyzed on Affymetrix arrays versus FFPE DASL). RESULTS: The correlation between FFPE and frozen survival signature estimates was 0.774. The TCGA signature using DASL was predictive of survival in 106 advanced stage high grade serous ovarian cancers (median survival 33 versus 60 months, estimated hazard ratio for death 2.30, p=0.0007). Similar to Tothill, we found using DASL that most high grade serous ovarian cancers (102/110, 93%) were assigned to subtypes 1, 2, 4 and 5, whereas most endometrioid, clear cell, mucinous and low grade serous cases (39/57, 68%) were assigned to subtypes 3 and 6 (p<10e-15). CONCLUSIONS: Although individual probe estimates of microarrays may be weakly correlated between FFPE and frozen samples, combinations of probes have robust ability to predict survival and subtype. This suggests that it may be possible to use these signatures for prognostic and predictive purposes as we seek to individualize the treatment of ovarian cancer.
  Gynecologic Oncology 12/2012; · 3.89 Impact Factor