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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.

SUBMITTER: Mauland KK

PROVIDER: S-EPMC5354764 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Aneuploidy related transcriptional changes in endometrial cancer link low expression of chromosome 15q genes to poor survival.

Mauland Karen Klepsland KK Wik Elisabeth E Hoivik Erling A EA Kusonmano Kanthida K Halle Mari Kyllesø MK Berg Anna A Haugland Hans Kristian HK Øyan Anne Margrete AM Kalland Karl-Henning KH Stefansson Ingunn Marie IM Akslen Lars A LA Krakstad Camilla C Trovik Jone J Werner Henrica Maria Johanna HM Salvesen Helga Birgitte HB

Oncotarget 20170201 6

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 ...[more]

PMID: 28039471

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Project description:Recent developments in molecular cytogenetics allow the detection of genomic rearrangements at an unprecedented level leading to discoveries of previously unknown chromosomal imbalances (zygotic and post-zygotic/mosaic). These can be accompanied by a different kind of pathological genome variations, i.e. chromosome instability (CIN) manifested as structural chromosomal rearrangements and low-level mosaic aneuploidy. Fortunately, combining whole-genome and single-cell molecular cytogenetic techniques with bioinformatics offers an opportunity to link genomic changes to specific molecular or cellular pathology. High-resolution chromosomal SNP microarray analysis was performed to study the genome of a 15-month-aged boy presented with developmental delay, congenital malformations, feeding problems, deafness, epileptiform activity, and eye pathology. In addition, somatic chromosomal mutations (CIN) were analyzed by fluorescence in situ hybridization (FISH). Interstitial 5p13.3p13.2 duplication was revealed in the index patient. Moreover, CIN manifested almost exclusively as chromosome losses and gains (aneuploidy) was detected. Using bioinformatic analysis of SNP array data and FISH results, CIN association with the genomic imbalance resulted from the duplication was proposed. The duplication was demonstrated to encompass genes implicated in cell cycle, programmed cell death, chromosome segregation and genome stability maintenance pathways as shown by an interactomic analysis. Genotype-phenotype correlations were observed, as well. To the best our knowledge, identical duplications have not been reported in the available literature. Apart from genotype-phenotype correlations, it was possible to propose a link between the duplication and CIN (aneuploidy). This case study demonstrates that combining SNP array genomic analysis, bioinformatics and molecular cytogenetic evaluation of somatic genome variations is able to provide a view on cellular and molecular pathology in a personalized manner. Therefore, one can speculate that similar approaches targeting both interindividual and intercellular genomic variations could be useful for a better understanding of disease mechanisms and disease-related biological processes.

Dataset Information

Aneuploidy related transcriptional changes in endometrial cancer link low expression of chromosome 15q genes to poor survival.

Publications

Aneuploidy related transcriptional changes in endometrial cancer link low expression of chromosome 15q genes to poor survival.

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