High-Grade Cervical Intraepithelial Neoplasia (CIN) Associates with Increased Proliferation and Attenuated Immune Signaling.

Irene Tveiterås Øvestad,Saleha Akbari,Morten Lapin,Einar G Gudlaugsson,Melinda Lillesand,Emiel A M Janssen,Marie Austdal,Birgit Engesæter,Marit Nordhus,Ane Cecilie Munk,Beatrix Bicskei,Camilla Krakstad,Mari Kyllesø Halle

doi:10.3390/ijms23010373

Abstract

Implementation of high-risk human papilloma virus (HPV) screening and the increasing proportion of HPV vaccinated women in the screening program will reduce the percentage of HPV positive women with oncogenic potential. In search of more specific markers to identify women with high risk of cancer development, we used RNA sequencing to compare the transcriptomic immune-profile of 13 lesions with cervical intraepithelial neoplasia grade 3 (CIN3) or adenocarcinoma in situ (AIS) and 14 normal biopsies from women with detected HPV infections. In CIN3/AIS lesions as compared to normal tissue, 27 differential expressed genes were identified. Transcriptomic analysis revealed significantly higher expression of a number of genes related to proliferation, (CDKN2A, MELK, CDK1, MKI67, CCNB2, BUB1, FOXM1, CDKN3), but significantly lower expression of genes related to a favorable immune response (NCAM1, ARG1, CD160, IL18, CX3CL1). Compared to the RNA sequencing results, good correlation was achieved with relative quantitative PCR analysis for NCAM1 and CDKN2A. Quantification of NCAM1 positive cells with immunohistochemistry showed epithelial reduction of NCAM1 in CIN3/AIS lesions. In conclusion, NCAM1 and CDKN2A are two promising candidates to distinguish whether women are at high risk of developing cervical cancer and in need of frequent follow-up.

Highlights

IntroductionMost cervical cancers are caused by a persistent infection with high-risk human papillomavirus (HPV) [1]
Introduction distributed under the terms andmost cervical cancers are caused by a persistent infection with high-risk human papillomavirus (HPV) [1]
Additional cervical sample results from the corresponding women were collected from their medical records

Summary

Introduction

Most cervical cancers are caused by a persistent infection with high-risk human papillomavirus (HPV) [1]. During their lifetime, the vast majority of sexually active women incur an HPV infection, but less than 10% develop persistent infection associated with a higher risk of developing cervical cancer [2]. Invasive cervical cancer is preceded by a conditions of the Creative Commons. Long phase of pre-invasive disease named cervical intraepithelial neoplasia (CIN). In Norway, there is a general increase in the prevalence of HPV, and a significant increase in the number of diagnosed CIN2/3 has been observed in the last 25 years [3]. CIN is classified as a pre-cancer, even though only approximately 9% of CIN1 will progress to CIN3 [4], and approximately 30% of CIN3 progress to cancer [5], while 20 to 40% of CIN3 will regress spontaneously [4,6,7]

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