Molecular profiles and tumor mutational burden analysis in Chinese patients with gynecologic cancers

Author:Min Wang, Chen Tian, Mingxia Ye, Lili Zhao, Wensheng Fan, Jianfei Wang, Wenbo Han, Wen Yang, Chenglei Gu, Mingxia Li, Zhe Zhang, Henghui Zhang, Yuanguang Meng

Background: Gynecologic cancers account for approximately 18% of all female cancers. Since management options for advanced gynecologic cancers are limited, immune checkpoint blockade is a potential therapy to be investigated in several clinical trials. Despite being an emerging biomarker of sensitivity to immune checkpoint inhibitors, the tumor mutational burden (TMB) in Chinese patients with gynecologic cancer has not been well characterized yet. 

Methods: In total, 117 patients with gynecologic cancers were included in this study. Both tumor DNA and paired blood cell genomic DNA were isolated from formalin-fixed paraffin-embedded (FFPE) specimens and blood samples and subjected to enrichment for a 1.15 Mb-panel representing exonic regions from 1086 genes, followed by next-generation sequencing on an Illumina X10 platform. The captured sequencing data were further subjected to bioinformatics analysis to identify somatic mutations, including single nucleotide variants (SNVs) and short insertions/deletions (indels). In addition, TMB values were evaluated and analyzed. 

Results: TP53, PTEN, ARID1A, and PIK3CA alterations were significantly different in various types of gynecologic cancers (p=0.001, 1.15E-07, 0.004, and 0.009, respectively). The median TMB of all 117 gynecologic tumor specimens was 0.37 mutations/Mb, with a range of 0-41.45 mutations/Mb. Despite the lack of significant difference, endometrial cancer cases had a higher median TMB than did cervical and ovarian cancer cases (p=0.81). Younger gynecologic cancer patients (age<40 years) had a significantly lower TMB than did older patients (age≥40 years) (p=0.04). 

In addition, TMB was significantly increased with increasing clinical stage of disease (p=0.001). PTEN alterations were commonly observed in patients with a moderate to high TMB (n=8, 38.10%, p=9.95E-04). Although limited by sample size, all of the patients with TSC2 (n=3, p=3.83E-11) or POLE (n=2, p=0.005) mutations had a moderate to high TMB. 

Conclusions: Patients with mutations in the PTEN, TSC2 or POLE gene have increased TMB. However, further large-scale, prospective studies are needed to validate our findings.