Identifying Potential Neoantigens for Cervical Cancer Immunotherapy Using Comprehensive Genomic Variation Profiling of Cervical Intraepithelial Neoplasia and Cervical Cancer.

Chaohui Bao,Hong Xie,Ling Xu,Na An,Jun Luo,Boping Zhou,Jian Huang,Wanqiu Huang

doi:10.3389/fonc.2021.672386

Abstract

Cervical cancer (CC) is one of the most common gynecological malignant tumors. The 5-year survival rate remains poor for the advanced and metastatic cervical cancer for the lack of effective treatments. Immunotherapy plays an important role in clinical tumor therapy. Neoantigens derived from tumor-specific somatic mutations are prospective targets for immunotherapy. Hence, the identification of new targets is of great significance for the treatment of advanced and metastatic cervical cancer. In this study, we performed whole-exome sequencing in 70 samples, including 25 cervical intraepithelial neoplasia (CINs) with corresponding blood samples and 10 CCs along with paired adjacent tissues to identify genomic variations and to find the potential neoantigens for CC immunotherapy. Using systematic bioinformatics pipeline, we found that C>T transitions were in both CINs and CCs. In contrast, the number of somatic mutations in CCs was significantly higher than those in CINs (t-test, P = 6.60E-04). Meanwhile, mutational signatures analysis revealed that signature 6 was detected in CIN2, CIN3, and CC, but not in CIN1, while signature 2 was only observed in CCs. Furthermore, PIK3CA, ARHGAP5 and ADGRB1 were identified as potential driver genes in this report, of which ADGRB1 was firstly reported in CC. Based on the genomic variation profiling of CINs and CCs, we identified 2586 potential neoantigens in these patients, of which 45 neoantigens were found in three neoantigen-related databases (TSNAdb, IEDB, and CTDatabase). Our current findings lay a solid foundation for the study of the pathogenesis of CC and the development of neoantigen-targeted immunotherapeutic measures.

Highlights

Cervical cancer (CC) is one of the most common gynecological malignant tumors, second only to breast cancer, which occupies the second place in the incidence of women’s malignant tumors in China
The average number of mutations was 330.5 in CCs, which was significantly higher than that in CIN1 (6.45), CIN2 (6.80), or CIN3 (9.67), respectively (Kruskal-Wallis chi-squared test, P = 8.13E-05). These results showed that the number of somatic mutations was distinctly increasing from cervical intraepithelial neoplasia (CINs) to CCs (Figure 2A, upper panel and Supplementary Table 3)
We identified that the somatic mutations at IGF2R were deemed to highly damaging and the exome-derived neoantigens were detected in both CINs and CCs

Summary

Introduction

Cervical cancer (CC) is one of the most common gynecological malignant tumors, second only to breast cancer, which occupies the second place in the incidence of women’s malignant tumors in China. There are about half a million new cases of CC every year, and more than 80% of these cases are in developing countries [1, 2]. Early diagnosis, and early treatment are the keys to the treatment of CC. Some patients with early cervical cancer can be cured through surgery, chemotherapy, etc. Platinum-based chemotherapy regimens, including cisplatin, carboplatin, fluorouracil, and paclitaxel, are often used in patients with CC [3]. Many patients with advanced cervical cancer and those with metastases to other tissues and organs have a poor prognosis. The identification of new targets for treatments of CC, especially for immunotherapy, is of great significance for the treatment of advanced and metastatic cervical cancer

Methods

Results

Conclusion