STAT3 polymorphisms may predict an unfavorable response to first‐line platinum‐based therapy for women with advanced serous epithelial ovarian cancer

Abstract

Cancer stem cells (CSC) contribute to epithelial ovarian cancer (EOC) progression and therapeutic response. We hypothesized that germline single nucleotide polymorphisms (SNPs) in CSC-related genes may predict an initial therapeutic response for women newly diagnosed with EOC. A nested case–control design was used to study 361 women with advanced-stage serous EOC treated with surgery followed by first-line platinum-based combination therapy at Moffitt Cancer Center or as part of The Cancer Genome Atlas Study. “Cases” included 102 incomplete responders (IRs) and “controls” included 259 complete clinical responders (CRs) to therapy. Using Illumina genotyping arrays and imputation, DNA samples were evaluated for 5,509 SNPs in 24 ovarian CSC-related genes. We also evaluated the overall significance of each CSC gene using the admixture maximum likelihood (AML) test, and correlated genotype with EOC tumor tissue expression. The strongest SNP-level associations with an IR to therapy were identified for correlated (r2 > 0.80) SNPs within signal transducer and activator of transcription 3 (STAT3) [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.32–3.78; p = 0.0027], after adjustment for age, population stratification, grade and residual disease. At the gene level, STAT3 was significantly associated with an IR to therapy (pAML 5 0.006). rs1053004, a STAT3 SNP in a putative miRNA-binding site, was associated with STAT3 expression (p = 0.057). This is the first study to identify germline STAT3 variants as independent predictors of an unfavorable therapeutic response for EOC patients. Findings suggest that STAT3 genotype may identify high-risk women likely to respond more favorably to novel therapeutic combinations that include STAT3 inhibitors.

JAK2/STAT3 pathway as a therapeutic target in ovarian cancers

“…In ovarian cancers, some reports suggested have reported that the activation of STAT3 was associated with prognoses by univariate analysis (10,11). In serous histological subtype, a report revealed that STAT3 polymorphisms were associated with unfavorable responses against platinum-based chemotherapy (12). In clear-cell subtype, it has been reported that IL-6R, an activator of JAK2/STAT3 signaling, was correlated with unfavorable survival by multivariate analysis, however, no relationship between prognoses and activation of phosphorylated STAT3 (p-STAT3) was observed (13).…”

Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci

“…STAT3 is over-activated in ovarian cancer cells and inhibition is subsequently accompanied by tumor growth suppression(64). Additionally, the Jak /STAT3 pathway has been linked with cancer cell survival and chemoresistance(65, 66) and recent work suggests germline polymorphisms within STAT3 predict poor response to platinum-based therapy(67). Lastly, PAX8 is a member of the paired box family of transcription factors (PAX1-9) that are primarily expressed in the embryo with persistent expression observed in ovarian tumors(68).…”

STAT3 signaling in ovarian cancer: a potential therapeutic target

“…These results are in parallel with the findings that it increases toxicity of cisplatin or paclitaxel to ovarian cancer when treated with JAK2 or STAT3 inhibitor, such as AG490 79, 80 , WP1066 79,80 , Diindolylmethane 39 , SD-1029 45 , and SD-1008 46 . Moreover, a recent study reveals that STAT3 polymorphisms may function as an independent marker predicting a poor response to chemotherapy for patients with advanced serous EOC 82 .…”