Gene Expression Indicates Altered Immune Modulation and Signaling Pathway Activation in Ovarian Cancer Patients Resistant to Topotecan.

Otília Menyhárt,János Tibor Fekete,Balázs Győrffy

doi:10.3390/ijms20112750

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.

Highlights

Ovarian cancer accounts for 2.5% of cancer diagnoses and 5% of cancer-related deaths among women worldwide
Data from 1436 patients diagnosed with epithelial ovarian cancer (EOC) were available from 10 datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) repositories [18,19,20,21,22,23,24,25,26,27]
In relapsed patients treated with chemotherapy, upregulated genes were specific to the extracellular matrix and collagen fibril organization, skeletal system development, cellular response to fibroblast growth factor stimulus and collagen catabolic processes

Summary

Introduction

Ovarian cancer accounts for 2.5% of cancer diagnoses and 5% of cancer-related deaths among women worldwide. The most common subgroup, epithelial ovarian cancer (EOC), represents about 90% of all ovarian cancer cases. A lack of specific symptoms, late diagnoses and intrinsic and acquired resistance to most conventional chemotherapies designate EOC as one of the deadliest cancers among women, with 5-year survival rates as low as 50% [3]. Over 70% of patients are diagnosed in an advanced disease stage with intraperitoneal dissemination [4]. The most common subtype, serous ovarian carcinoma, represents about 50% of all EOC, with most diagnosed at stage III (51%) or stage IV (29%), with 5-year survival rates of 20%, reflecting the subtype’s aggressive nature [1]

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