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Article

Signal Transduction Pathway Activity in High-Grade, Serous Ovarian Carcinoma Reveals a More Favorable Prognosis in Tumors with Low PI3K and High NF-κB Pathway Activity: A Novel Approach to a Long-Standing Enigma

1
Department of Obstetrics and Gynecology, Catharina Cancer Institute, Catharina Hospital, 5602ZA Eindhoven, The Netherlands
2
Radboud Institute for Health Sciences, Department of Obstetrics and Gynecology, Radboud University Medical Center, 6500HB Nijmegen, The Netherlands
3
Precision Diagnostics, Philips Research, 5656AE Eindhoven, The Netherlands
4
Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne 3000, Australia
5
Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney 2145, Australia
*
Author to whom correspondence should be addressed.
The author on behalf of the Australian Ovarian Cancer Study Group.
Cancers 2020, 12(9), 2660; https://doi.org/10.3390/cancers12092660
Received: 4 August 2020 / Revised: 9 September 2020 / Accepted: 11 September 2020 / Published: 18 September 2020
(This article belongs to the Special Issue High-Grade Serous Ovarian Cancer)
All cells have a complex internal network of ‘communication chains’ called signal transduction pathways (STPs). Through interaction of different proteins in STPs, they are partly responsible for the behavior of a cell. In our study, we investigated the activity of eight STPs in datasets with genetic information on 140 cancer samples. These samples were derived from the most common subtype of ovarian cancer: high grade serous ovarian carcinoma (HGSC). With a novel method, we determined which STPs were active and discerned two groups based on activity of the phosphoinositide 3-kinase (PI3K) and nuclear factor-kappa B (NF-kB) pathways. The group with low PI3K and high NF-kB activity had a better progression free and overall survival compared to the group with high PI3K and low NF-kB activity. This difference may indicate that the ‘better prognosis group’ had a more active immune system or that the cells divided at a slower rate.
We investigated signal transduction pathway (STP) activity in high-grade serous ovarian carcinoma (HGSC) in relation to progression-free survival (PFS) and overall survival (OS). We made use of signal transduction pathway activity analysis (STA analysis), a novel method to quantify functional STP activity. Activity of the following pathways was measured: androgen receptor (AR), estrogen receptor (ER), phosphoinositide 3-kinase (PI3K), Hedgehog (Hh), Notch, nuclear factor-kappa B (NF-κB), transforming growth factor beta (TGF-β), and Wnt. We selected HGSC samples from publicly available datasets of ovarian cancer tissue, and used repeated k-means clustering to identify pathway activity clusters. PFS and OS of the clusters were analyzed. We used a subset of publicly available dataset GSE9891 (n = 140), where repeated k-means clustering based on PI3K and NF-κB pathway activity in HGSC samples resulted in two stable clusters. The cluster with low PI3K and high NF-κB pathway activity (n = 72) had a more favorable prognosis for both PFS (p = 0.004) and OS (p = 0.001) compared to the high-PI3K and low-NF-κB pathway activity cluster (n = 68). The low PI3K and high NF-κB pathway activity of the favorable prognosis cluster may indicate a more active immune response, while the high PI3K and low NF-κB pathway activity of the unfavorable prognosis cluster may indicate high cell division. View Full-Text
Keywords: high-grade serous ovarian cancer; epithelial ovarian cancer; signal transduction pathways; progression-free survival; cluster analysis high-grade serous ovarian cancer; epithelial ovarian cancer; signal transduction pathways; progression-free survival; cluster analysis
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MDPI and ACS Style

van Lieshout, L.; van de Stolpe, A.; van der Ploeg, P.; Bowtell, D.; de Hullu, J.; Piek, J. Signal Transduction Pathway Activity in High-Grade, Serous Ovarian Carcinoma Reveals a More Favorable Prognosis in Tumors with Low PI3K and High NF-κB Pathway Activity: A Novel Approach to a Long-Standing Enigma. Cancers 2020, 12, 2660. https://doi.org/10.3390/cancers12092660

AMA Style

van Lieshout L, van de Stolpe A, van der Ploeg P, Bowtell D, de Hullu J, Piek J. Signal Transduction Pathway Activity in High-Grade, Serous Ovarian Carcinoma Reveals a More Favorable Prognosis in Tumors with Low PI3K and High NF-κB Pathway Activity: A Novel Approach to a Long-Standing Enigma. Cancers. 2020; 12(9):2660. https://doi.org/10.3390/cancers12092660

Chicago/Turabian Style

van Lieshout, Laura, Anja van de Stolpe, Phyllis van der Ploeg, David Bowtell, Joanne de Hullu, and Jurgen Piek. 2020. "Signal Transduction Pathway Activity in High-Grade, Serous Ovarian Carcinoma Reveals a More Favorable Prognosis in Tumors with Low PI3K and High NF-κB Pathway Activity: A Novel Approach to a Long-Standing Enigma" Cancers 12, no. 9: 2660. https://doi.org/10.3390/cancers12092660

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