Diagnostic and prognostic values of the mRNA expression of excision repair cross-complementation enzymes in hepatitis B virus-related hepatocellular carcinoma

Figures & data

Table 1 Distribution of HCC patients’ characteristics and prognosis analysis

Variables	RFS				OS
	Events/total	MRT (months)	HR (95% CI)	Log-rank P	Events/total	MST (months)	HR (95% CI)	Log-rank P
Age (years)				0.916				0.629
≤60	96/175	46	1		69/175	NA	1
>60	20/37	48	0.974 (0.602–1.578)		13/37	NA	0.864 (0.478–1.564)
Gender				0.018				0.148
Male	106/183	40	1		74/183	NA	1
Female	10/29	NA	0.467 (0.244–0.893)		8/29	NA	0.587 (0.283–1.218)
Cirrhosis				0.029				0.025
No	5/17		1		2/17	NA	1
Yes	111/195	38	2.612 (1.066–6.402)		80/195	NA	4.335 (1.065–17.638)
Tumor sizea				0.073				0.002
≤5 cm	73/137	51	1		46/137	NA	1
>5 cm	43/74	28	1.409 (0.966–2.056)		36/74	53	1.975 (1.274–3.060)
Multinodular				0.381				0.052
Single	90/167	49	1		59/167	NA	1
Multiple	26/45	28	1.216 (0.785–1.883)		23/45	48	1.607 (0.992–2.604)
BCLC stage				<0.001				<0.001
0	6/20	NA	1		2/20	NA	1
A	74/143	51	2.050 (0.892–4.711)		48/143	NA	4.119 (1.001–16.951)
B	15/22	27	4.019 (1.550–10.421)		12/22	46	8.992 (2.005–40.320)
C	21/27	9	6.163 (2.477–15.333)		20/27	13	18.993 (4.419–81.632)
TNM stage				<0.001				<0.001
I	35/89	NA	1		20/89	NA	1
II	48/76	28	1.995 (1.289–3.088)		32/76	NA	2.214 (1.265–3.873)
III	33/47	18	3.220 (1.993–5.204)		30/47	18	5.197 (2.930–9.218)
CLIP stage				0.001				<0.001
0	46/94	57	1		26/94	NA	1
1	37/71	40	1.197 (0.776–1.846)		25/71	NA	1.414 (0.816–2.449)
2/3/4/5	33/47	19	2.233 (1.424–3.500)		31/47	27	3.638 (2.153–6.149)
Serum AFPb				0.327				0.047
≤300 ng/mL	62/115	48	1		39/115	NA	1
>300 ng/mL	54/94	35	1.200 (0.833–1.728)		43/94	NA	1.546 (1.002–2.385)

Notes:

a Information of tumor size was unavailable in one patient.

b Information of serum AFP was unavailable in three patients.

Abbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; HCC, hepatocellular carcinoma; MRT, median recurrence time; MST, median survival time; OS, overall survival; RFS, recurrence-free survival.

Figure 1 Gene expression distribution of ERCC genes in GSE14520 HBV-related HCC cohort.

Notes: ***P<0.001; ****P<0.0001.

Abbreviations: ERCC, excision repair cross-complementation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

Figure 2 Gene expression distribution of ERCC gene in liver cancer using the MERAV.

Note: The order of box plots of ERCC genes were as follows: ERCC1 (A), ERCC2 (B), ERCC3 (C), ERCC4 (D), ERCC5 (E), ERCC6 (F), and ERCC8 (G).

Abbreviations: ERCC, excision repair cross-complementation; MERAV, Metabolic gEne RApid Visualizer.

Figure 3 ROC curves of ERCC genes in distinguish HBV-related HCC tissue from adjacent normal liver tissue.

Note: The order of ROC curves of ERCC genes were as follows: ERCC1 (A), ERCC2 (B), ERCC3 (C), ERCC4 (D), ERCC5 (E), ERCC6 (F), and ERCC8 (G).

Abbreviations: AUC, area under the curve of ROC; ERCC, excision repair cross-complementation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; ROC, receiver-operating characteristic.

Table 2 Survival analysis of ERCC genes in HBV-related HCC prognosis

Gene expression	Patients (n=212)	MST/MRT (months)	Crude HR (95% CI)	Crude P	Adjusted HR (95% CI)	Adjusted Pa
RFS		MRT
ERCC1
Low	106	40	1		1
High	106	49	0.903 (0.627–1.300)	0.583	1.061 (0.723–1.556)	0.762
ERCC2
Low	106	35	1		1
High	106	49	0.854 (0.593–1.229)	0.396	0.934 (0.646–1.351)	0.717
ERCC3
Low	106	46	1		1
High	106	46	1.059 (0.735–1.524)	0.759	1.173 (0.805–1.710)	0.405
ERCC4
Low	106	36	1		1
High	106	53	0.706 (0.489–1.019)	0.063	0.818 (0.560–1.194)	0.298
ERCC5
Low	106	41	1		1
High	106	46	1.066 (0.740–1.535)	0.731	0.952 (0.651–1.392)	0.798
ERCC6
Low	106	30	1		1
High	106	54	0.704 (0.448–1.016)	0.061	0.768 (0.527–1.118)	0.168
ERCC8
Low	106	30	1		1
High	106	57	0.613 (0.424–0.887)	0.009	0.643 (0.442–0.937)	0.021
OS		MST
ERCC1
Low	106	NA	1		1
High	106	NA	0.864 (0.560–1.334)	0.509	1.040 (0.663–1.630)	0.865
ERCC2
Low	106	NA	1		1
High	106	NA	0.805 (0.522–1.243)	0.328	0.865 (0.558–1.343)	0.518
ERCC3
Low	106	NA	1		1
High	106	NA	1.303 (0.844–2.012)	0.233	1.511 (0.961–2.375)	0.074
ERCC4
Low	106	NA	1		1
High	106	NA	0.637 (0.410–0.989)	0.044	0.729 (0.465–1.142)	0.167
ERCC5
Low	106	NA	1		1
High	106	NA	1.067 (0.691–1.647)	0.77	0.899 (0.572–1.412)	0.643
ERCC6
Low	106	58	1		1
High	106	NA	0.654 (0.421–1.015)	0.059	0.723 (0.462–1.133)	0.157
ERCC8
Low	106	54	1		1
High	106	NA	0.549 (0.351–0.858)	0.008	0.631 (0.399–0.998)	0.049

Note:

a Adjustment for age, gender, cirrhosis, tumor size, tumor number, BCLC stage, and serum AFP level.

Abbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; ERCC, excision repair cross-complementation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; MRT, median recurrence time; MST, median survival time; OS, overall survival; RFS, recurrence-free survival.

Table 3 Stratified survival analysis of ERCC8 in HBV-related HCC prognosis

Variables	Patients (n=218)	Low ERCC8	High ERCC8	RFS		OS
				Adjusted HR (95% CI)	Adjusted Pa	Adjusted HR (95% CI)	Adjusted Pa
Age (years)
≤60	175	88	87	0.694 (0.456–1.055)	0.087	0.659 (0.396–1.098)	0.11
>60	37	18	19	0.498 (0.172–1.442)	0.199	0.506 (0.133–1.926)	0.318
Gender
Male	183	91	92	0.664 (0.447–0.984)	0.041	0.647 (0.398–1.053)	0.08
Female	29	15	14	0.099 (0.007–1.319)	0.08	0.140 (0.011–1.844)	0.135
Cirrhosis
No	17	6	11	1×10e^−6 (1.8×10e^−196–3.7×10e^183)	0.952	4.9×10e^−5 (6.9×10e^−20–3.7×10e^Citation10)	0.57
Yes	195	100	95	0.673 (0.458–0.988)	0.043	0.676 (0.425–1.075)	0.098
Tumor sizeb
≤5 cm	137	63	74	0.705 (0.437–1.136)	0.151	0.575 (0.306–1.081)	0.086
>5 cm	74	42	32	0.570 (0.292–1.114)	0.1	0.757 (0.363–1.579)	0.458
Multinodular
Single	167	81	86	0.618 (0.406–0.939)	0.024	0.524 (0.309–0.888)	0.016
Multiple	45	25	20	0.837 (0.305–2.298)	0.73	1.575 (0.533–4.659)	0.411
BCLC stage
0	20	9	11	0.592 (0.101–3.457)	0.561	7×10e^−6 (2.64×10e^−264–1.7×10e^245)	0.968
A	143	65	78	0.755 (0.475–1.199)	0.234	0.684 (0.385–1.216)	0.196
B	22	14	8	0.473 (0.123–1.815)	0.275	1.006 (0.238–4.263)	0.993
C	27	18	9	0.893 (0.291–2.734)	0.842	0.981 (0.312–3.083)	0.973
TNM stage
I	89	37	52	0.533 (0.266–1.068)	0.076	0.553 (0.223–1.372)	0.201
II	76	39	37	0.807 (0.438–1.488)	0.492	0.987 (0.472–2.064)	0.973
III	47	30	17	1.057 (0.459–2.435)	0.897	1.081 (0.440–2.655)	0.866
CLIP stage
0	94	40	54	0.827 (0.455–1.503)	0.532	0.735 (0.330–1.639)	0.452
1	71	35	36	0.681 (0.340–1.364)	0.278	0.509 (0.218–1.189)	0.119
2/3/4/5	47	31	16	0.411 (0.159–1.061)	0.066	0.978 (0.391–2.448)	0.962
Serum AFPc
≤300 ng/mL	115	52	63	0.860 (0.516–1.432)	0.562	0.737 (0.386–1.405)	0.354
>300 ng/mL	94	53	41	0.422 (0.232–0.767)	0.005	0.512 (0.259–1.016)	0.055

Notes:

a Adjustment for age, gender, cirrhosis, tumor size, tumor number, BCLC stage, and serum AFP level.

b Information of tumor size was unavailable in one patient.

c Information of serum AFP was unavailable in three patients.

Abbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; ERCC, excision repair cross-complementation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; OS, overall survival; RFS, recurrence-free survival.

Table 4 Joint effect survival analysis of ERCC8 and serum AFP in HBV-related HCC prognosis

Group	AFP levela	ERCC8 expression	Patients (n=209)	MRT/MST (months)	Crude HR (95% CI)	Crude P	Adjusted HR (95% CI)	Adjusted Pb
RFS	Serum (ng/mL)			MRT
Group A	>300	Low	53	23	1		1
Group B	>300	High	41	NA	0.448 (0.252–0.795)	0.006	0.426 (0.237–0.768)	0.004
Group C	<300	Low	52	48	0.671 (0.414–1.086)	0.104	0.656 (0.398–1.081)	0.098
Group D	<300	High	63	51	0.546 (0.340–0.877)	0.012	0.583 (0.354–0.962)	0.035
OS				MST
Group a	>300	Low	53	36	1		1
Group b	>300	High	41	NA	0.463 (0.242–0.889)	0.021	0.522 (0.268–1.018)	0.057
Group c	<300	Low	52	NA	0.575 (0.329–1.005)	0.052	0.661 (0.369–1.185)	0.165
Group d	<300	High	63	NA	0.401 (0.223–0.719)	0.002	0.499 (0.268–0.927)	0.028
RFS	mRNA			MRT
Group I	High	Low	60	21	1		1
Group II	High	High	46	NA	0.389 (0.224–0.673)	0.001	0.418 (0.238–0.734)	0.002
Group III	Low	Low	46	51	0.519 (0.313–0.859)	0.011	0.425 (0.238–0.757)	0.004
Group IV	Low	High	60	53	0.524 (0.331–0.830)	0.006	0.443 (0.259–0.757)	0.003
OS				MST
Group i	High	Low	60	47	1		1
Group ii	High	High	46	NA	0.400 (0.206–0.775)	0.007	0.533 (0.267–1.063)	0.074
Group iii	Low	Low	46	NA	0.602 (0.339–1.069)	0.083	0.612 (0.308–1.215)	0.161
Group iv	Low	High	60	NA	0.478 (0.272–0.841)	0.01	0.487 (0.249–0.952)	0.035

Notes:

a Information of serum AFP was unavailable in three patients.

b Adjustment for age, gender, cirrhosis, tumor size, tumor number, BCLC stage, and serum AFP level.

Abbreviations: AFP, alpha-fetoprotein; ERCC, excision repair cross-complementation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; MRT, median recurrence time; MST, median survival time; OS, overall survival; RFS, recurrence-free survival.

Figure 4 Kaplan–Meier curves of ERCC genes in HBV-related HCC RFS.

Note: The order of Kaplan–Meier curves of ERCC genes were as follows: ERCC1 (A), ERCC2 (B), ERCC3 (C), ERCC4 (D), ERCC5 (E), ERCC6 (F), and ERCC8 (G).

Abbreviations: ERCC, excision repair cross-complementation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; RFS, recurrence-free survival.

Figure 5 Kaplan–Meier curves of ERCC genes in HBV-related HCC OS.

Note: The order of Kaplan–Meier curves of ERCC genes were as follows: ERCC1 (A), ERCC2 (B), ERCC3 (C), ERCC4 (D), ERCC5 (E), ERCC6 (F), and ERCC8 (G).

Abbreviations: ERCC, excision repair cross-complementation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; OS, overall survival.

Figure 6 Joint effect survival analysis of ERCC8 and AFP in HBV-related HCC prognosis.

Notes: (A) RFS stratified by ERCC8 and serum AFP level; (B) OS stratified by ERCC8 and serum AFP level; (C) RFS stratified by ERCC8 and AFP mRNA level; and (D) OS stratified by ERCC8 and serum AFP mRNA level.

Abbreviations: AFP, alpha-fetoprotein; ERCC, excision repair cross-complementation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; OS, overall survival; RFS, recurrence-free survival.

Figure 7 Nomogram for predicting the 1-, 3-, and 5-year event with ERCC8 expression and clinical indicators.

Notes: (A) Nomogram for ERCC8 expression in HBV-related HCC RFS. (B) Nomogram for ERCC8 expression in HBV-related HCC OS.

Abbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; ERCC, excision repair cross-complementation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; OS, overall survival; RFS, recurrence-free survival.

Figure 8 GSEA results of ERCC8.

Notes: (A)–(F) GSEA results of c2 reference gene sets for high ERCC8 expression. (G)–(I) GSEA results of c5 reference gene sets for high ERCC8 expression.

Abbreviations: ERCC, excision repair cross-complementation; GSEA, gene set enrichment analysis; FDR, false discovery rate; ES, Enrichment Score; NES, Normalized Enrichment Score.

Figure 9 Coexpression genes of ERCC8 in HBV-related HCC.

Figure 10 GO term enrichments of coexpression genes of ERCC8 in HBV-related HCC.

Abbreviations: ERCC, excision repair cross-complementation; GO, Gene Ontology; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

Notes: The green nodes represent negative correlation with ERCC8, and the red nodes represent positive correlation with ERCC8.

Abbreviations: ERCC, excision repair cross-complementation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

Figure 10 GO term enrichments of coexpression genes of ERCC8 in HBV-related HCC.

Abbreviations: ERCC, excision repair cross-complementation; GO, Gene Ontology; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

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