title: The O-glycan pathway is associated with in vitro sensitivity to gemcitabine             and overall survival from ovarian cancer.
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.
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center                     and Research Institute, Tampa, FL 33612, USA.
authors.forename: Nadim
authors.initials: N
authors.lastname: Bou Zgheib
authors.forename: Yin
authors.initials: Y
authors.lastname: Xiong
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Marchion
authors.forename: Elona
authors.initials: E
authors.lastname: Bicaku
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Chon
authors.forename: Xiaomang Ba
authors.initials: XB
authors.lastname: Stickles
authors.forename: Entidhar Al
authors.initials: EA
authors.lastname: Sawah
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Judson
authors.forename: Ardeshir
authors.initials: A
authors.lastname: Hakam
authors.forename: Jesus
authors.initials: J
authors.lastname: Gonzalez-Bosquet
authors.forename: Robert M
authors.initials: RM
authors.lastname: Wenham
authors.forename: Sachin M
authors.initials: SM
authors.lastname: Apte
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cubitt
authors.forename: Dung Tsa
authors.initials: DT
authors.lastname: Chen
authors.forename: Johnathan M
authors.initials: JM
authors.lastname: Lancaster
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D053898:Biosynthetic Pathways / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006031:Glycosylation; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D011134:Polysaccharides / Q000096:biosynthesis; D025341:Principal Component Analysis; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D015398:Signal Transduction; D014158:Transcription, Genetic; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D011134:Polysaccharides; D003841:Deoxycytidine; D000093542:Gemcitabine