Host chemokine signature as a biomarker for the detection of pre-cancerous cervical lesions.

Ramya Bhatia,Itziar Serrano,Alistair R.W Williams,Camille Busby-Earle,Juergen G Haas,June Stewart,Sharon Moncur,Duanduan Cong,Kate Cuschieri,Kim Kavanagh,Sarah E.M Howie,Heather A Cubie

doi:10.18632/oncotarget.24946

Abstract

BackgroundThe ability to distinguish which hrHPV infections predispose to significant disease is ever more pressing as a result of the increasing move to hrHPV testing for primary cervical screening. A risk-stratifier or “triage” of infection should ideally be objective and suitable for automation given the scale of screening.ResultsCCL2, CCL3, CCL4, CXCL1, CXCL8 and CXCL12 emerged as the strongest, candidate biomarkers to detect underlying disease [cervical intraepithelial neoplasia grade 2 or worse (CIN2+)]. For CIN2+, CCL2 had the highest area under the curve (AUC) of 0.722 with a specificity of 82%. A combined biomarker panel of six chemokines CCL2, CCL3, CCL4, CXCL1, CXCL8, and CXCL12 provides a sensitivity of 71% and specificity of 67%.ConclusionThe present work demonstrates that the levels of five chemokine-proteins are indicative of underlying disease. We demonstrate technical feasibility and promising clinical performance of a chemokine-based biomarker panel, equivalent to that of other triage options. Further assessment in longitudinal series is now warranted.MethodsA panel of 31 chemokines were investigated for expression in routinely taken archived and prospective cervical liquid based cytology (LBC) samples using Human Chemokine Proteomic Array kit. Nine chemokines were further validated using Procartaplex assay on the Luminex platform.

Highlights

Persistent infection with high-risk Human Papilloma Virus causes >95% of cervical cancers [1]
CCL2, CCL3, CCL4, CXCL1, CXCL8 and CXCL12 emerged as the strongest, candidate biomarkers to detect underlying disease [cervical intraepithelial neoplasia grade 2 or worse (CIN2+)]
For CIN2+, CCL2 had the highest area under the curve (AUC) of 0.722 with a specificity of 82%

Summary

Introduction

Persistent infection with high-risk (oncogenic) Human Papilloma Virus (hrHPV) causes >95% of cervical cancers [1]. Cervical hrHPV infection is common but most infections clear naturally. In a small proportion of women, infection persists and persistent infection can lead to the development of cervical lesions referred to as cervical intraepithelial neoplasia (CIN grades 1 to 3 according to increasing severity) [2, 3]. If left untreated a proportion of lesions will develop into cervical cancer. Around thirteen hrHPV types cause 99% of all cervical cancers. The ability to distinguish which hrHPV infections predispose to significant disease is ever more pressing as a result of the increasing move to hrHPV testing for primary cervical screening. A risk-stratifier or “triage” of infection should ideally be objective and suitable for automation given the scale of screening

Objectives

Methods

Results

Conclusion