Features of the cervicovaginal microenvironment drive cancer biomarker signatures in patients across cervical carcinogenesis

Paweł Łaniewski,David L Greenspan,Denise J Roe,Dana M Chase,Dominique Barnes,Bradley J Monk,Alison Goulder,Haiyan Cui,Melissa M Herbst-Kralovetz

doi:10.1038/s41598-019-43849-5

Abstract

Persistent human papillomavirus (HPV) infection is the vital factor driving cervical carcinogenesis; however, other features of the local cervicovaginal microenvironment (CVM) may play a critical role in development of precancerous cervical dysplasia and progression to invasive cervical carcinoma (ICC). Here we investigated relationships between locally secreted cancer biomarkers and features of the local CVM to better understand the complex interplay between host, virus and vaginal microbiota (VMB). We enrolled women with ICC, high- and low-grade squamous intraepithelial lesions, as well as, HPV-positive and healthy HPV-negative controls. A broad range of cancer biomarkers was present in the local CVM and specifically elevated in ICC patients. The majority of cancer biomarkers were positively correlated to other biomarkers and linked to genital inflammation. Several cancer biomarkers were also negatively correlated to Lactobacillus abundance and positively correlated with abnormal vaginal pH. Finally, a hierarchical clustering analysis of cancer biomarkers and immune mediators revealed three patient clusters, which varied in levels of cancer biomarkers, genital inflammation, vaginal pH and VMB composition. Specific cancer biomarkers discriminated patients with features of the CVM, such as high genital inflammation, elevated vaginal pH and dysbiotic non-Lactobacillus-dominant VMB, that have been associated with HPV persistence, dysplasia and progression to ICC.

Highlights

Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide, with an estimated 14.1 million new cases in the United States annually[1]
To better understand the impact of vaginal microbiota (VMB) on the local cervicovaginal microenvironment (CVM), we examined a broad panel of known circulating cancer biomarkers in cervicovaginal lavages (CVL) collected from patients with cervical cancer or cervical dysplasia, as well as, healthy human papillomavirus (HPV)-positive and HPV-negative women without neoplasia
The analysis revealed that expression of cancer biomarkers in the local CVM is related to cervical carcinoma

Summary

Introduction

Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide, with an estimated 14.1 million new cases in the United States annually[1]. It is well documented that persistent HPV infection is the vital factor driving the development of precancerous cervical intraepithelial neoplasia (CIN) and progression to invasive cervical carcinoma (ICC)[5,6,7,8,9,10] Several cofactors such as smoking, age of sexual debut, high parity, long-term use of contraceptives, hormone treatment and co-infections with sexually transmitted pathogens have been shown to be associated with progression of cervical neoplasia among HPV-infected women[11,12,13]. Numerous epidemiological studies have shown associations between the dysbiotic non-Lactobacillus-dominant (NLD) VMB and HPV infection, development of precancerous dysplasia and progression to cervical cancer[14,15,16,17,18,19,20,21,22,23,24,30]. One longitudinal study found an association of L. gasseri with HPV clearance[19]

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Conclusion