Gene expression data reveal common pathways that characterize the unifocal nature of ovarian cancer

Abstract

Objective: The objective of the study was to evaluate the biological validity of ovarian cancer (OVCA) screening and early detection efforts and to characterize signaling pathways associated with human cancer metastasis and patient survival.

Study design: Using genome-wide expression profiling and deoxyribonucleic acid sequencing, we compared pelvic and matched extrapelvic implants from 30 patients with advanced-stage OVCA for expression of molecular signaling pathways and p53 gene mutations. Differentially expressed pathways were further evaluated in a series of primary or early-stage vs metastatic or recurrent cancer samples from 389 ovarian, prostate, and oral cancer patients. Metastasis pathways were also evaluated for associations with survival in 9 independent clinicogenomic datasets from 1691 ovarian, breast, colon, brain, and lung cancer and leukemia patients. The inhibitory effects of 1 pathway (transforming growth factor [TGF]-WNT) on in vitro OVCA cell migration were studied.

Results: Pelvic and extrapelvic OVCA implants demonstrated similar patterns of signaling pathway expression and identical p53 mutations. However, we identified 3 molecular pathways/cellular processes that were differentially expressed between pelvic and extrapelvic OVCA samples and between primary/early-stage and metastatic/advanced or recurrent ovarian, oral, and prostate cancers. Furthermore, their expression was associated with overall survival from ovarian cancer (P = .006), colon cancer (1 pathway at P = .005), and leukemia (P = .05). Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration.

Conclusion: Advanced-stage OVCA has a unifocal origin in the pelvis. Molecular pathways associated with extrapelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease.

Keywords: gene expression; p53 mutation; serous ovarian cancer; unifocal.

Figure 1

Comparison of overall expression profiles across all samples. Results for principal component analyses (PCA) of gene expressions in normal ovarian surface epithelium (NOSE; green circles), primary pelvic (filled blue circles), and extra-pelvic (yellow triangles) samples are shown. The first principal component (PC1) explains 35.4% of the variation, whereas the second (PC2) explains 6.3%.

Figure 2

The TGF-WNT/cytoskeleton remodeling pathway is associated with survival from OVCA, colon cancer, and leukemia. (A) TGF-WNT/cytoskeleton remodeling pathway. Thermometers indicate the directional change (upward or downward) in expression of genes associated with extra-pelvic implant samples. Numbers 1–2 at base identify the originating dataset (1 = grouped analysis, unique to NOSE versus extra-pelvic implant; 2 = individual analysis; common to ≥15 paired samples). (B–D) Kaplan-Meier curves depicting the association between the TGF-WNT/cytoskeleton remodeling-pathway PCA score (using median PCA threshold) and overall survival from OVCA (GSE9891, survival information available for 218 of the 220 samples) (B), colon cancer (GSE17538, n=177 (C), and leukemia (TCGA database, n=182 (D). Log-rank test P values indicate significance.

Figure 3

The chemokines/cell adhesion pathway is associated with survival from colon cancer. A, Chemokines/cell adhesion pathway. Thermometers indicate the directional change (upward or downward) in expression of genes associated with extra-pelvic implant samples. Numbers 1–2 at base identify the originating dataset (1 = grouped analysis, unique to NOSE versus extra-pelvic implant; 2 = individual analysis; common to ≥15 paired samples). B, Kaplan-Meier curves depicting the association between the chemokines/cell adhesion pathway PCA score (using median PCA threshold) and overall survival from colon cancer (GSE17538, n=177). Log-rank test P values indicate significance.

Figure 4

The Histamine signaling/immune response pathway is associated with survival from OVCA and colon cancer. A, Histamine signaling/immune response pathway. Thermometers indicate the directional change (upward or downward) in expression of genes associated with extra-pelvic implant samples. Numbers 1–2 at base identify the originating dataset (1 = grouped analysis, unique to NOSE versus extra-pelvic implant; 2 = individual analysis, common to ≥15 paired samples). B and C, Kaplan-Meier curves depicting the association between the chemokines/cell adhesion pathway PCA score (using median PCA threshold) and overall survival from OVCA (MCC dataset, n=142) and colon cancer (GSE17538, n=177), respectively. Log-rank test P values indicate significance.

Figure 5

TGF-WNT/cytoskeleton remodeling pathway inhibition prevents OVCA cell migration. HeyA8 cells treated with 25 μM and 50 μM artesunate (ART) were impaired in their ability to fill in the gap of a scratch test. In contrast, cells cultured in the presence of DMSO vehicle completely closed the gap within 2 days.