Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer

Heidi Lyng,Olav Kaalhus,Runar S Brøvig,Gunnar B Kristensen,Ruth Holm,Kolbein Sundfør,Debbie H Svendsrud,Halldis Oksefjell,Kjetil Knutstad,Trond Stokke

doi:10.1186/1471-2164-7-268

Abstract

BackgroundA better understanding of the development of metastatic disease and the identification of molecular markers for cancer spread would be useful for the design of improved treatment strategies. This study was conducted to identify gene expressions associated with metastatic phenotypes of locally advanced cervical carcinomas and investigate whether gains or losses of these genes could play a role in regulation of the transcripts. Gene expressions and copy number changes were determined in primary tumors from 29 patients with and 19 without diagnosed lymph node metastases by use of cDNA and genomic microarray techniques, respectively.ResultsThirty-one genes that differed in expression between the node positive and negative tumors were identified. Expressions of eight of these genes (MRPL11, CKS2, PDK2, MRPS23, MSN, TBX3, KLF3, LSM3) correlated with progression free survival in univariate analysis and were therefore more strongly associated with metastatic phenotypes than the others. Immunohistochemistry data of CKS2 and MSN showed similar relationships to survival. The prognostic genes clustered into two groups, suggesting two major metastatic phenotypes. One group was associated with rapid proliferation, oxidative phosphorylation, invasiveness, and tumor size (MRPS23, MRPL11, CKS2, LSM3, TBX3, MSN) and another with hypoxia tolerance, anaerobic metabolism, and high lactate content (PDK2, KLF3). Multivariate analysis identified tumor volume and PDK2 expression as independent prognostic variables. Gene copy number changes of the differentially expressed genes were not frequent, but correlated with the expression level for seven genes, including MRPS23, MSN, and LSM3.ConclusionGene expressions associated with known metastatic phenotypes of cervical cancers were identified. Our findings may indicate molecular mechanisms underlying development of these phenotypes and be useful as markers of cancer spread. Gains or losses of the genes may be involved in development of the metastatic phenotypes in some cases, but other mechanisms for transcriptional regulation are probably important in the majority of tumors.

Highlights

A better understanding of the development of metastatic disease and the identification of molecular markers for cancer spread would be useful for the design of improved treatment strategies
Thirty-one genes with major difference in expression when comparing the data of node positive and negative tumors, were selected. These were 16 genes with higher and 15 with lower expression in the node positive tumors (Figure 1A) and included genes coding for structural proteins, such as the mitochondrial ribosomal proteins MRPS23 and MRPL11, enzymes participating in metabolism, like the pyruvate dehydrogenase kinase PDK2 and the hexokinase HK2, proteins interacting with the extracellular matrix, such as moesin (MSN) and the hyaluronglucosaminidase HYAL1, the cell division cycle CDC28 protein kinase regulatory subunit 2 (CKS2), the proteinase inhibitor cystatin A (CSTA), and others with multiple or more unclear functions with regard to metastasis development, like the hypothetical proteins MGC14151, LSM3, and FLJ13291, the muscleblind-like protein MBNL2, the T-box transcription factor TBX3, the krüppel-like factor KLF3, the annexin ANXA4, and the myocyte enhancer factor MEF2A (Table 1)
We report 31 genes that differed in expression between lymph node positive and negative tumors, as diagnosed from magnetic resonance (MR) images

Summary

Introduction

A better understanding of the development of metastatic disease and the identification of molecular markers for cancer spread would be useful for the design of improved treatment strategies. Lymph node involvement is the first indication of spreading and a strong prognostic factor for epithelial cancers [1]. A better understanding of the development of metastatic tumor phenotypes and the identification of molecular markers for lymphatic spread would be useful in design of improved treatment strategies [2]. Cervical carcinomas have been studied extensively during the last years in the search for biological characteristics that are associated with lymph node involvement. A more comprehensive characterization of the tumors is, needed to achieve a complete understanding of how metastatic phenotypes develop in cervical cancers

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