Evaluation of Vav3.1 as prognostic marker in endometrial cancer

Maximilian Boesch,Daniel Reimer,Dominik Wolf,Jiri Hatina,Heidi Fiegl,Alain G Zeimet,Julia Rössler,Sieghart Sopper,Christian Marth,Annemarie Wiedemair

doi:10.1007/s00432-018-2725-2

Abstract

PurposeVav3 is a guanine nucleotide exchange factor that regulates the activity of Rho/Rac family GTPases. In a study on ovarian cancer, we recently demonstrated pronounced prognostic and predictive value of Vav3.1, a specific truncation variant of the parental Vav3 gene. Here, we sought to investigate the role of Vav3.1 in the most prevalent gynecological tumor entity, endometrial cancer.MethodsVav3.1 transcript levels were determined in a large cohort of endometrial cancer patients using variant-specific PCR (n = 239), and non-malignant endometrial tissue served as control (n = 26). Expression levels of Vav3.1 were stratified according to established clinicopathological characteristics and correlated to long-term patient survival (average follow-up of > 7.5 years). Type 1 and type 2 cancers were separately investigated.ResultsWhile Vav3.1 was markedly overexpressed in endometrial cancer tissue, we could not detect associations with clinical parameters related to prognosis, such as FIGO stage and tumor grade. Kaplan–Meier estimators of different measures of survival failed to show prognostic significance of Vav3.1 in endometrial cancer. Lack of prognostic value was observed for both type 1 and type 2 cancers.ConclusionsOur study shows that Vav3.1 is not suited as a marker of cancer progression and/or treatment response in endometrial cancer. Feasibility and potential benefit of targeting Vav3.1 in endometrial cancer needs to be evaluated in future studies, proceeding from its clear, roughly ten-fold, induction in the malignant endometrium.

Highlights

Endometrial cancer (EC) is the most prevalent gynecological malignancy and has traditionally been classified into two major subtypes that differ in histological appearance and clinical behavior (Hecht and Mutter 2006)
We found that Vav2, which was measured in a sub-fraction of patients (n = 90), was only marginally upregulated in the cancer specimens (1.12-fold increase, p = 0.0387)
Overexpression of Vav3/Vav3.1 was pronounced in type 1 and type 2 cancers (Fig. 1c, d), indicating a common mechanism of Vav3 activation among principal EC subentities

Summary

Introduction

Endometrial cancer (EC) is the most prevalent gynecological malignancy and has traditionally been classified into two major subtypes that differ in histological appearance and clinical behavior (Hecht and Mutter 2006). Type 2 cancers are of non-endometrioid histology (usually serous or clear cell), depend on hormone stimulation to a lesser extent, typically arise in the aged atrophic endometrium, and are often poorly differentiated (Hecht and Mutter 2006; Setiawan et al 2013). Certain patient subgroups exhibit poor outcome despite low-risk classification according to Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) staging, and filtering out these individuals is critical to consider additional therapeutic options early on preventing undertreatment of a whole patient subset (Zeimet et al 2013)

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Results

Conclusion