Overexpression of MUC16 predicts favourable prognosis in MUC16-mutant cervical cancer related to immune response

Abstract

Cervical cancer (CC) is the fourth ranking gynaecologic tumour in women worldwide, with respect to both incidence and mortality. MUC16 is one of the most frequently mutated genes, which functions as a tumour marker in CC. In the present study, mutation, clinical and RNA-Seq data collected from The Cancer Genome Atlas database were used to investigate the association between MUC16 mutation, immune response and clinical prognosis in CC. mRNA expression levels from the TCGA datasets and the results from the present study demonstrated that MUC16 was overexpressed in CC samples; however, there was no difference between mutant and wild-type CC samples. Furthermore, the results indicated that patients with MUC16-mutant overexpression had a prolonged survival time. In addition, overexpression of MUC16 was associated with immune responses in the microenvironment of MUC16-mutant CC. Immune responses were upregulated in patients with early-stage MUC16-mutant. The results from the present study provided novel biomarkers for potential immunotherapy approaches for CC.

Keywords: MUC16; cervical cancer; cervical squamous cell carcinoma; immune response; mutation.

Figure 1

Landscape of MUC16 mutations in CC. (A) An OncoPlot of the top 10 mutated genes in CC samples from TCGA database. The upper bar plot indicates the number of genetic mutations/patient, while the bar plot on the right indicates the number of genetic mutations/gene. The CC pathology types and mutation types are represented as annotations at the bottom. (B) A lollipop plot of MUC16 mutations in CC samples from TCGA database. Amino acid axis labelled for domain. (C) Proportions of MUC16 mutations between endocervical adenocarcinoma and cervical squamous cell carcinoma. (D) Proportions of different types of single nucleotide variants of MUC16 in CC samples from TCGA database. (E) Numbers of different types of single nucleotide variants of MUC16 in CC samples from TCGA database. CC, cervical cancer; TCGA, The Cancer Genome Atlas; TTN, Titin; PIK3CA, phosphatidylinositol 3; MUC4, mucoprotein 4; KMT2C, histone lysine methyltransferase 2C; MUC16, mucoprotein 16; KMT2D, histone lysine methyltransferase 2D; FLG, filaggrin; DMD, duchenne muscular dystrophy; EP300, E1A binding protein p300; SYNE1, spectrin repeat-containing nuclear envelope protein 1.

Figure 2

Landscape of MUC16 expression in CC. (A) Bar plot of FPKM for LINC00265 in different types of cancer from TCGA database. Data are presented as the mean ± SEM. (B) Left panel: Bar plot depicting MUC16 expression in CC and normal samples from the GSE9750 dataset. Right panel: Expression levels of MUC16-mutated and MUC16-wild-type samples of CC from TCGA database. Data are presented as the mean ± SEM. (C) MUC16 protein levels were determined via western blotting for normal and CC samples (top), and mutant and wild-type CC samples (bottom). (D) Association between CNV level and MUC16 expression in MUC16-mutated and MUC16-wild-type samples. (E) Association between DNA methylation level and MUC16 expression in MUC16-mutated and MUC16-wild-type samples. CC, cervical cancer; FPKM, fragments per kilobase million; TCGA, The Cancer Genome Atlas; SEM, standard error of the mean; CNV, copy number variation.

Figure 3

Overexpression of MUC16 was associated with favourable prognosis of patients with CC and mutant MUC16. Kaplan-Meier plots depicting the OS, DSS and PFS time in patients with (A) MUC16-mutant, (B) MUC16-wild-type and (C) all patients with CC from TCGA database. Kaplan-Meier plots depicting the OS, DSS and PFS time in patients with (D) MUC16-mutant, (E) MUC16-wild-type and (F) all patients with cervical squamous cell carcinoma from TCGA database. CC, cervical cancer; OS, overall survival; DSS, disease-specific survival; PFS, progression-free survival; TCGA, The Cancer Genome Atlas; HR, hazard ratio.

Figure 4

MUC16 mutations were involved in immune responses. (A) Volcano plot depicting the NES and negative logarithmically transformed P-value of immune response-associated gene sets in MUC16-mutant and MUC16-wild-type CC samples from TCGA database. Enrichment of (B) B cell-associated and (C) T cell-associated gene sets with overexpression of MUC16, in MUC16-wild-type and MUC16-mutant CC samples from TCGA database. (D) Bar plots depicting the activity level of multiple immune responses in different disease stages between MUC16-mutant and MUC16-wild-type samples of CC from TCGA database. Data are presented as the mean ± standard error of the mean. NES, normalized enrichment score; CC, cervical cancer; TCGA, The Cancer Genome Atlas.