Identification of a Six-Gene Signature for Predicting the Overall Survival of Cervical Cancer Patients

Figures & data

Table 1 Top 20 Most Significant Prognostic Genes

Gene	HR	Coefficient	z Score	p value
ENSG00000135917	1.748677971	0.558860057	4.436721804	9.13E-06
ENSG00000163421	1.682368397	0.520202561	4.376242475	1.21E-05
ENSG00000000005	1.513401732	0.41435992	4.361855389	1.29E-05
ENSG00000162604	1.501643857	0.406560412	4.099799021	4.14E-05
ENSG00000196468	1.673950164	0.515186201	3.960270954	7.49E-05
ENSG00000164588	1.537245105	0.429991922	3.940550485	8.13E-05
ENSG00000117335	2.46589333	0.902554147	3.865969034	0.000110649
ENSG00000172023	1.529686885	0.425063064	3.797280694	0.000146292
ENSG00000113327	1.513257567	0.414264656	3.784384898	0.000154089
ENSG00000226490	1.444495797	0.367760331	3.772939226	0.000161336
ENSG00000185730	1.973737202	0.679928802	3.734920178	0.000187775
ENSG00000214686	1.424691673	0.35395542	3.729554952	0.000191818
ENSG00000162736	2.603303699	0.956781292	3.723143696	0.000196757
ENSG00000204007	1.472298714	0.386824931	3.696985142	0.000218175
ENSG00000214107	1.557528566	0.443100312	3.690028732	0.000224229
ENSG00000118702	11.76746014	2.465338107	3.641055676	0.000271522
ENSG00000204979	1.544184328	0.434495828	3.61125427	0.00030472
ENSG00000197275	1.563705433	0.447058282	3.602161044	0.000315583
ENSG00000168843	1.379657366	0.321835183	3.599920612	0.000318314
ENSG00000180708	1.388555784	0.328264203	3.560948718	0.000369517

Figure 1 (A) Significantly amplified segments in the CC genome. (B) Significantly deleted segments in the CC genome. (C) The top 50 genes with the most significant p values. The upper histogram represents the total number of synonymous and nonsynonymous mutations in the 50 genes from each patient, and the right histogram represents the mutation proportion of 50 genes in all samples. (D) A total of 839 genes with significant copy number variation and mutations were included in the KEGG pathway analysis. (E) A total of 839 genes with significant CNV and mutations were included in the GO biological process analysis. (F) The relationship between prediction error rates and the number of separate trees. (G) The out-of-bag importance rank of the top 6 genes.

Table 2 6-Genes Significantly Associated with the Overall Survival in the Training-Set Patients

Ensembl Gene ID	Symbol	HR	Z-score	P value	Importance	Relative Importance
ENSG00000102970	CCL17	0.44	−3.100495	1.93E-03	0.0193	1
ENSG00000135917	SLC19A3	1.75	4.436722	9.13E-06	0.0185	0.9583
ENSG00000140564	FURIN	1.53	2.163624	3.05E-02	0.0117	0.6042
ENSG00000175084	DES	0.52	−2.476295	1.33E-02	0.0105	0.5417
ENSG00000146477	SLC22A3	1.59	2.498738	1.25E-02	0.0101	0.5208
ENSG00000172269	DPAGT1	1.65	2.65869	7.84E-03	0.0097	0.5

Figure 2 (A) Kaplan–Meier survival curve of patients stratified according to the 6-gene signature in the TCGA training dataset. (B) ROC curve and AUC of the 6-gene signature. (C) Risk score, survival period and gene expression level. (D) The nomogram prediction of OS.

Figure 3 (A) Kaplan–Meier survival curve of patients stratified according to the 6-gene signature in the TCGA test dataset. (B) ROC curve and AUC of the 6-gene signature. (C) Risk score, survival period and gene expression level.

Figure 4 (A) Kaplan–Meier survival curve of patients stratified according to the 6-gene signature in independent validation dataset. (B) ROC curve and AUC of the 6-gene signature. (C) Risk score, survival period and gene expression level.

Table 3 Univariate and Multivariate Cox Regression Analysis to Verify the Independence of 6-Gene Signature in Test Datasets

Variables	Univariate Analysis			Multivariable Analysis
	HR	95% CI of HR	P value	HR	95% CI of HR	P value
Validation cohort,TCGA test datasets, GSE44001
TCGA test datasets
6-gene risk score
Low risk group	1(reference)			1(reference)
High risk group	1.25	1.04–1.49	0.016	1.444	1.05–1.97	0.020
Age	1.01	0.98–1.03	0.463	0.988	0.94–1.02	0.560
Grade 1	1(reference)			1(reference)
Grade 2	1.37	0.31–5.89	0.674	1.340	0.14–12.11	0.794
Grade 3	1.51	0.34–6.67	0.59	1.12	0.12–9.88	0.919
Pathologic T 1	1(reference)			1(reference)
Pathologic T 2	0.97	0.37–2.49	0.943	0.17	0.017–1.72	0.135
Pathologic T 3	0.78	0.17–3.40	0.742	1.150	0.20–6.58	0.875
Pathologic T 4	11.68	3.20–42.48	1.92E-04	231.567	7.16–7483.09	0.002
Pathologic N 0	1(reference)			1(reference)
Pathologic N 1	3.48	1.5–8.06	0.004	10.266	3.30–31.88	0.000
Pathologic M 0	1(reference)			1(reference)
Pathologic M 1/M X	1.90	0.91–3.94	8.50E-02	1.341	0.48–3.69	0.570
Tumor stage I	1(reference)			1(reference)
Tumor stage II	0.73	0.29–1.801	0.498	7.57	0.49–114.99	0.145
Tumor stage ш/IV	1.31	0.60–2.81	0.49	0.446	0.05–3.92	0.467
GSE44001
6-gene risk score
Low risk group	1(reference)			1(reference)
High risk group	1.40	1.09–1.79	0.007	1.40	1.09–1.78	0.007
Tumor stage I	1(reference)			1(reference)
Tumor stage II	1.71	0.78–3.73	0.180	1.75	0.80–3.82	0.158

Figure 5 IHC for CCL17, DES, DPAGT1, FURIN, SLC19A3 and SLC22A3. CC-adjacent tissue (N=30) and CC tissue (N=130) samples. CC-adjacent tissue samples with weak immunostaining scores for DPAGT1 (G), FURIN (J), SLC19A3 (M), and SLC22A3 (P) and strong immunostaining scores for CCL17 (A) and DES (D). CC samples with weak and strong immunostaining scores for CCL17 (B and C), DES (E and F), DPAGT1 (H and I), FURIN (K and L), SLC19A3 (N and O) and SLC22A3 (Q and R). The expression of the CCL17, DES, DPAGT1, FURIN, SLC19A3 and SLC22A3 genes is depicted in S slides (X 100). **p < 0.01, ***p < 0.001.

Figure 6 OS and PFS curves for CC (N=130) according to CCL17 (A and B), DES (C and D), DPAGT1 (E and F), FURIN (G and H), SLC19A3 (I and J) and SLC22A3 (K and L) gene expression status (low or high). The expression status for each sample was classified according to the median gene expression value.