Cervical cancer is the second-leading cause of cancer death in women globally, with a disproportionate burden on developing countries. Human papilloma virus (HPV) vaccination will not eliminate cervical cancer in the short term, so screening programs will remain essential for decades. HPV DNA testing is a highly sensitive screening method now being implemented in more settings, but its low specificity mandates triage (secondary) testing for positively screened women to avoid overtreatment harms which may include adverse pregnancy and fertility outcomes. Currently, triage options in low income settings are limited. Specific biomarkers that could be readily detected during the patient encounter through in vivo imaging present a novel promising triage strategy. The discovery of membrane biomarkers of cervical cancer and precancerous lesions may therefore enable the development of specific, sensitive, low cost in vivo detection tests for prevalent precancers.
The Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED), which includes approximately 3000 women referred for colposcopy from 2003 to 2011 with abnormal screening results, was designed to investigate cervical carcinogenesis and improve the ability to predict which women with HPV infections and low-grade lesions will progress to cancer. Gene expression levels were determined from mRNA microarrays of SUCCEED tissue from 128 patients at all stages of progression to cervical cancer (1), and differential expression of genes across the spectrum of normal, cervical intraepithelial neoplasia (CIN), and cancerous tissues (alpha=0.05 for cancer vs normal expression and for CIN vs normal expression) was detected.
Based on the above criteria, 48 genes encoding for proteins with membrane-bound Gene Ontology annotations that could be amenable to in vivo staining and visualization were identified. Nineteen genes were prioritized for further investigation according to plausibility of plasma membrane localization, altered expression during early carcinogenesis, cervical expression, antibody availability, and enzymatic activity, of which 15 had increased and four had decreased expression in CIN tissues.
Validation of candidate proteins through immunohistochemical staining of SUCCEED tissues is currently under way, which will be followed by the investigation of the in vivo imaging potential of validated candidates using both antibody-based and enzyme-activated optical imaging methods. Finally, promising candidates will be moved forward to clinical studies evaluating their clinical utility for triage to immediate treatment after positive cervical cancer screening results.
1. den Boon JA, et al. (2015) Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling. Proc Natl Acad Sci U S A 112(25):E3255-3264.