H2A Histone Family Member X (H2AX) Is Upregulated in Ovarian Cancer and Demonstrates Utility as a Prognostic Biomarker in Terms of Overall Survival.

Sayeh Saravi,Hasnat A Amin,Fotios Drenos,Jeyarooban Jeyaneethi,Kazuaki Takabe,Marcia Hall,George Pados,Eriko Katsuta,Matthias Kaspar,Emmanouil Karteris

doi:10.3390/jcm9092844

Abstract

Background: H2AX can be of prognostic value in breast cancer, since in advanced stage patients with high levels, there was an association with worse overall survival (OS). However, the clinical relevance of H2AX in ovarian cancer (OC) remains to be elucidated. Methods: OC H2AX expression studied using the TCGA/GTEX datasets. Subsequently, patients were classified as either high or low in terms of H2AX expression to compare OS and perform gene set enrichment. qRT-PCR validated in-silico H2AX findings followed by immunohistochemistry on a tissue microarray. The association between single nucleotide polymorphisms in the area of H2AX; prevalence and five-year OC survival was tested in samples from the UK Biobank. Results: H2AX was significantly overexpressed in OCs compared to normal tissues, with higher expression associated with better OS (p = 0.010). Gene Set Enrichment Analysis demonstrated gene sets involved in G2/M checkpoint, DNA repair mTORC1 signalling were enriched in the H2AX highly expressing OCs. Polymorphisms in the area around the gene were associated with both OC prevalence (rs72997349-C, p = 0.005) and worse OS (rs10790282-G, p = 0.011). Finally, we demonstrated that H2AX gene expression correlated with γ-H2AX staining in vitro. Conclusions: Our findings suggest that H2AX can be a novel prognostic biomarker for OC.

Highlights

An acquired or inherited deficiency in DNA repair pathways in humans can lead to an increased lifetime risk of cancer
ClinE.xMperde. 2s0s2io0,n9,oxfFHOR2APEXER(oRrEVHIE2WAFX) was significantly upregulated in the primary and recur5reonf 1t8 ovarian cancer when compared to normal tissues in TCGA (Figure 1A). qRT-PCR in a small cohort of sotafgsetaIIgIeovIIaIrioavnacraianncecrapnacteirenptas tcioenntfisrmcoendfihrmigheder heixgphreersseioxnproefsHsi2oAnXofwHhe2nAXcomwphaernedcotomapgaeremdattcohaegde cmonattrcohlsed(Fciognutrreo1lsB()F. igure 1B)
We examined the number of γ-H2AX foci in BRCA wild-type and mutant ovarian cancer (OC) cell lines to investigate whether BRCA2 mutant status impacts homologous recombination (HR) deficiency and effective repair of DNA DSB in vitro

Summary

Introduction

An acquired or inherited deficiency in DNA repair pathways in humans can lead to an increased lifetime risk of cancer. Examples of inheritable mutations in DNA repair genes which are known to increase the lifetime risk of cancers include BRCA1 and BRCA2. Certain mutations of these two well-characterized genes, result in a significant risk of breast and ovarian cancer in carriers, due to defective homologous recombination (HR), the principal mechanism for DSBs repair [2]. Gene Set Enrichment Analysis demonstrated gene sets involved in G2/M checkpoint, DNA repair mTORC1 signalling were enriched in the H2AX highly expressing OCs. Polymorphisms in the area around the gene were associated with both OC prevalence (rs72997349-C, p = 0.005) and worse OS (rs10790282-G, p = 0.011). Conclusions: Our findings suggest that H2AX can be a novel prognostic biomarker for OC

Methods

Results

Conclusion