Molecular profiling and clinical outcome of high-grade serous ovarian cancer presenting with low- versus high-volume ascites

Abstract

Epithelial ovarian cancer consists of multiple histotypes differing in etiology and clinical course. The most prevalent histotype is high-grade serous ovarian cancer (HGSOC), which often presents at an advanced stage frequently accompanied with high-volume ascites. While some studies suggest that ascites is associated with poor clinical outcome, most reports have not differentiated between histological subtypes or tumor grade. We compared genome-wide gene expression profiles from a discovery cohort of ten patients diagnosed with stages III-IV HGSOC with high-volume ascites and nine patients with low-volume ascites. An upregulation of immune response genes was detected in tumors from patients presenting with low-volume ascites relative to those with high-volume ascites. Immunohistochemical studies performed on tissue microarrays confirmed higher expression of proteins encoded by immune response genes and increased tumorinfiltrating cells in tumors associated with low-volume ascites. Comparison of 149 advanced-stage HGSOC cases with differential ascites volume at time of primary surgery indicated low-volume ascites correlated with better surgical outcome and longer overall survival. These findings suggest that advanced stage HGSOC presenting with low-volume ascites reflects a unique subgroup of HGSOC, which is associated with upregulation of immune related genes, more abundant tumor infiltrating cells and better clinical outcomes.

Figure 1

Gene expression profiling of a discovery cohort reveals an immune gene signature for HGSOC tumors presenting with low-volume ascites. Hierarchical clustering of patient samples based on 198 probes differentially expressed by ≥1.5-fold as determined by a moderated t-test (P < 0.05) in tumors associated with high- and low-volume ascites. Each line of the cluster tree shown at the top represents one patient sample. The ascites volume group is indicated by the bar at the bottom and by the line color. Magenta bars on the side indicate probes corresponding to the 20 genes that overlap with genes within the TCGA immunoreactive group and are upregulated in the low-volume ascites group.

Figure 2

Epithelial scoring for CD74, HLA-DR, TAP-2, and CD48 expression and immunohistochemical staining in representative cases of low- and high-volume ascites associated primary tumor samples. Immunohistochemistry was performed on tissue microarrays containing a total of 54 tumors associated with high- and low-volume ascites. Magnification 9x.

Figure 3

Comparison of clinical parameters of patients included in outcome analysis. P values shown in the table were determined by Fisher's exact test for categorical variables, the Wilcoxon rank-sum test continuous and ordered variables, and the long-rank test for days to death. n/a: statistical test not applied. The predicted probability of overall survival in patients with low- and high-volume ascites diagnosed with stages III-IV HGSOC is shown by the Kaplan-Meier plot. Data included in this plot were analyzed by a log-rank test.