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Gene Expression Indicates Altered Immune Modulation and Signaling Pathway Activation in Ovarian Cancer Patients
Otília Menyhárt1,2, János Tibor Fekete3,4, Balázs Győrffy5,6
12nd Department of Pediatrics, Semmelweis University, Tűzoltó u. 7-9, H-1094 Budapest, Hungary. menyhart.Otilia@med.semmelweis-univ.hu.
Abstract:
Epithelial ovarian cancer (EOC) is one of the deadliest gynecological malignancies. Topotecan remains an essential tool in second-line therapy; even so, most patients develop resistance within a short period of time. We aimed to identify biomarkers of topotecan resistance by using gene expression signatures derived from patient specimens at surgery and available subsequent responses to therapy. Gene expression was collected for 1436 patients and 10,103 genes. Based on disease progression, patients were categorized as responders/nonresponders depending on their progression free survival (PFS) state at 9, 12, 15 and 18 months after surgery. For each gene, the median expression was compared between responders and nonresponders for two treatment regimens (chemotherapy including/excluding topotecan) with Mann-Whitney U test at each of the four different PFS cutoffs. Statistical significance was accepted in the case of p < 0.05 with a fold change (FC) ≥ 1.44. Four genes (EPB41L2, HLA-DQB1, LTF and SFRP1) were consistently overexpressed across multiple PFS cutoff times in initial tumor samples of patients with disease progression following topotecan treatment. A common theme linked to topotecan resistance was altered immune modulation. Genes associated with disease progression after systemic chemotherapy emphasize the role of the initial organization of the tumor microenvironment in therapy resistance. Our results uncover biomarkers with potential utility for patient stratification.
Insights
Researchers identified four key genes (EPB41L2, HLA-DQB1, LTF, SFRP1) that indicate resistance to topotecan chemotherapy in epithelial ovarian cancer. These biomarkers may help predict patient response and stratify treatment strategies.
Area of Science:
- Gynecologic Oncology
- Translational Oncology
- Cancer Genomics
Background:
- Epithelial ovarian cancer (EOC) is a highly lethal gynecological malignancy.
- Topotecan is a critical second-line treatment, but resistance develops rapidly.
- Identifying biomarkers for topotecan resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To discover gene expression biomarkers associated with topotecan resistance in epithelial ovarian cancer.
- To correlate gene signatures with patient progression-free survival (PFS) after treatment.
Main Methods:
- Analyzed gene expression data from 1436 EOC patients and 10,103 genes.
- Compared gene expression between responders and non-responders at multiple PFS time points (9, 12, 15, 18 months).
- Utilized Mann-Whitney U test with statistical significance set at p < 0.05 and fold change (FC) ≥ 1.44.
Main Results:
- Four genes (EPB41L2, HLA-DQB1, LTF, SFRP1) were consistently overexpressed in patients progressing after topotecan treatment.
- Overexpression was observed across multiple PFS cutoffs in initial tumor samples.
- Altered immune modulation emerged as a common theme linked to topotecan resistance.
Conclusions:
- The identified genes (EPB41L2, HLA-DQB1, LTF, SFRP1) show potential as biomarkers for topotecan resistance in EOC.
- Tumor microenvironment organization plays a role in systemic chemotherapy resistance.
- These biomarkers could aid in patient stratification for personalized therapy.
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