Genomic instability influences the transcriptome and proteome in endometrial cancer subtypes

Jens K Habermann,Hans-Peter Bruch,Sampsa Hautaniemi,Danny Wangsa,Jana Doering,Timo Gemoll,Gert Auer,Hans Jörnvall,Britta Nordstroem,Nana K Bündgen,Thomas Ried,Caroline Lundgren,Uwe J Roblick

doi:10.1186/1476-4598-10-132

Abstract

BackgroundIn addition to clinical characteristics, DNA aneuploidy has been identified as a prognostic factor in epithelial malignancies in general and in endometrial cancers in particular. We mapped ploidy-associated chromosomal aberrations and identified corresponding gene and protein expression changes in endometrial cancers of different prognostic subgroups.MethodsDNA image cytometry classified 25 endometrioid cancers to be either diploid (n = 16) or aneuploid (n = 9), and all uterine papillary serous cancers (UPSC) to be aneuploid (n = 8). All samples were subjected to comparative genomic hybridization and gene expression profiling. Identified genes were subjected to Ingenuity pathway analysis (IPA) and were correlated to protein expression changes.ResultsComparative genomic hybridization revealed ploidy-associated specific, recurrent genomic imbalances. Gene expression analysis identified 54 genes between diploid and aneuploid endometrioid carcinomas, 39 genes between aneuploid endometrioid cancer and UPSC, and 76 genes between diploid endometrioid and aneuploid UPSC to be differentially expressed. Protein profiling identified AKR7A2 and ANXA2 to show translational alterations consistent with the transcriptional changes. The majority of differentially expressed genes and proteins belonged to identical molecular functions, foremost Cancer, Cell Death, and Cellular Assembly and Organization.ConclusionsWe conclude that the grade of genomic instability rather than the histopathological subtype correlates with specific gene and protein expression changes. The identified genes and proteins might be useful as molecular targets for improved diagnostic and therapeutic intervention and merit prospective validation.

Highlights

In addition to clinical characteristics, DNA aneuploidy has been identified as a prognostic factor in epithelial malignancies in general and in endometrial cancers in particular
Genomic instability Of the cancerous samples, 16 of the 25 endometrioid carcinomas showed diploid cell distribution pattern (EnD) and nine presented with aneuploid cell populations (EnA), while all eight uterine papillary serous cancers (UPSC) tumors were classified as aneuploid (UPSC-A)
The increasing degree of genomic instability in the EnA and UPSC-A groups compared to the EnD group was reflected in an increase in chromosomal copy number changes as measured by comparative genomic hybridization (CGH)

Summary

Introduction

In addition to clinical characteristics, DNA aneuploidy has been identified as a prognostic factor in epithelial malignancies in general and in endometrial cancers in particular. In carcinomas of the vagina the most frequent aberration detected is a gain of 3q [10], while in endometrial carcinomas, copy number gains were mapped to chromosome arms 1q, 3q, 8q, and 10q [11,12,13]. The predominance of these tumor entity specific chromosomal alterations leads to increased expression of resident genes that seems to be independent of tissue and/or cell type [14] and gives an irreversible disturbance of transcriptional regulation in aneuploid cells [15]

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Discussion

Conclusion