title: Aneuploidy related transcriptional changes in endometrial cancer link low expression of chromosome 15q genes to poor survival.
abstract: 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.
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway.|Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Karen Klepsland
authors.initials: KK
authors.lastname: Mauland
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Medicine (K1), Section for Pathology, University of Bergen, Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wik
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway.|Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Erling A
authors.initials: EA
authors.lastname: Hoivik
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.|Computational Biology Unit, University of Bergen, Bergen, Norway.|Bioinformatics and Systems Biology Program, School of Bioresources and Technology, King Mongkut's University of Technology Thonburi, Bangkhuntien, Bangkok, Thailand.
authors.forename: Kanthida
authors.initials: K
authors.lastname: Kusonmano
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway.|Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Mari Kyllesø
authors.initials: MK
authors.lastname: Halle
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway.|Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Anna
authors.initials: A
authors.lastname: Berg
authors.affiliation: Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Hans Kristian
authors.initials: HK
authors.lastname: Haugland
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway.|Department of Microbiology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Anne Margrete
authors.initials: AM
authors.lastname: Øyan
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway.|Department of Microbiology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Karl-Henning
authors.initials: KH
authors.lastname: Kalland
authors.affiliation: Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Ingunn Marie
authors.initials: IM
authors.lastname: Stefansson
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Medicine (K1), Section for Pathology, University of Bergen, Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway.|Center for Cancer Biomarkers CCBIO, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Camilla
authors.initials: C
authors.lastname: Krakstad
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway.|Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Jone
authors.initials: J
authors.lastname: Trovik
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway.|Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Henrica Maria Johanna
authors.initials: HM
authors.lastname: Werner
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway.|Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Helga Birgitte
authors.initials: HB
authors.lastname: Salvesen
mesh_terms: D000368:Aged; D000782:Aneuploidy; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D010641:Phenotype; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D012307:Risk Factors; D013997:Time Factors; D014158:Transcription, Genetic; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone
keywords: DNA ploidy; chromosome 15q; endometrial cancer; prognosis; transcriptional alterations