Aneuploidy related transcriptional changes in endometrial cancer link low expression of chromosome 15q genes to poor survival
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Karen Klepsland Mauland1,2, Elisabeth Wik3,4,*, Erling A. Hoivik1,2,*, Kanthida Kusonmano2,5,6, Mari Kyllesø Halle1,2, Anna Berg1,2, Hans Kristian Haugland4, Anne Margrete Øyan1,7, Karl-Henning Kalland1,7, Ingunn Marie Stefansson4, Lars A. Akslen3,4, Camilla Krakstad1,8, Jone Trovik1,2, Henrica Maria Johanna Werner1,2 and Helga Birgitte Salvesen1,2,**
1Center for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway
2Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
3Center for Cancer Biomarkers CCBIO, Department of Clinical Medicine (K1), Section for Pathology, University of Bergen, Bergen, Norway
4Department of Pathology, Haukeland University Hospital, Bergen, Norway
5Computational Biology Unit, University of Bergen, Bergen, Norway
6Bioinformatics and Systems Biology Program, School of Bioresources and Technology, King Mongkut’s University of Technology Thonburi, Bangkhuntien, Bangkok, Thailand
7Department of Microbiology, Haukeland University Hospital, Bergen, Norway
8Center for Cancer Biomarkers CCBIO, Department of Biomedicine, University of Bergen, Bergen, Norway
*These authors have contributed equally to this work
Karen Klepsland Mauland, email: Karen.Mauland@uib.no
Keywords: endometrial cancer, DNA ploidy, prognosis, transcriptional alterations, chromosome 15q
Received: October 06, 2016 Accepted: November 23, 2016 Published: December 25, 2016
Aneuploidy is a widely studied prognostic marker in endometrial cancer (EC), however, not implemented in clinical decision-making. It lacks validation in large prospective patient cohorts adjusted for currently standard applied prognostic markers, including estrogen/progesterone receptor status (ER/PR). Also, little is known about aneuploidy-related transcriptional alterations, relevant for understanding its role in EC biology, and as therapeutic target.
We included 825 EC patients with available ploidy status and comprehensive clinicopathologic characterization to analyze ploidy as a prognostic marker. For 144 patients, gene expression data were available to explore aneuploidy-related transcriptional alterations.
Aneuploidy was associated with high age, FIGO stage and grade, non-endometrioid histology, ER/PR negativity, and poor survival (p-values<0.001). In patients with ER/PR negative tumors, aneuploidy independently predicted poor survival (p=0.03), lymph node metastasis (p=0.007) and recurrence (p=0.002). A prognostic ‘aneuploidy signature’, linked to low expression of chromosome 15q genes, was identified and validated in TCGA data.
In conclusion, aneuploidy adds prognostic information in ER/PR negative EC, identifying high-risk patients that could benefit from more aggressive therapies. The ‘aneuploidy signature’ equally identifies these aggressive tumors and suggests a link between aneuploidy and low expression of 15q genes. Integrated analyses point at various dysregulated pathways in aneuploid EC, underlining a complex biology.
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