Abstract
Introduction A major impediment in the treatment of ovarian cancer is the relapse of platinum-resistant tumors, which occurs in approximately 25% of patients. A better understanding of the genetic mechanisms underlying response to platinum-based chemotherapy will improve treatment efficacy.
Objectives We used a systems biology approach to identify novel gene networks and regulatory sequence variants associated with platinum-based chemotherapy response.
Methods From the Cancer Genome Atlas (TCGA), we classified high-grade serous ovarian carcinoma (HGSOC) patients who remained cancer-free 12 months following completion of platinum-based chemotherapy as “chemo-sensitive” (N=160) and those who had cancer recurrence within six months of chemotherapy as “chemo-resistant” (N=110). Both univariate and multivariate analysis of gene expression microarrays identified differentially expressed genes and co-expression networks associated with chemotherapy response. Moreover, we integrated genomics data to determine expression quantitative trait loci (eQTL).
Results One differentially expressed gene encoding Valosin-containing protein (VCP) and five co-expression network modules were associated with chemotherapy response in HGSOC patients. These genes contribute to protein processing in the endoplasmic reticulum, which has been previously implicated in variable chemotherapy response. In addition, 192 eQTLs were associated with co-expressed gene modules as well as genes regulating cholesterol levels, also previously described to affect chemotherapy response.
Conclusion This study implicates known and novel gene networks underlying response to platinum-based chemotherapy among HGSOC patients. A better understanding of the genetic determinants of chemotherapy response will facilitate genetic testing for predicting drug response, which will increase treatment efficacy and identify patients for alternative therapies.