Association of FHIT expression and FHIT gene hypermethylation with liver cancer risk: a PRISMA-compliant meta-analysis

Figures & data

Figure 1 Flow diagram of the eligible literature search.

Abbreviation: FHIT, fragile histidine triad protein.

Table 1 Clinicopathological features of eligible studies

Author	Reference	Year	Country	Race	Histology	Control		Case		Methods	Control materials	Case materials	NOS score	Cut-off (%)
						Positive	Negative	Positive	Negative
Liu et al	23	2016	China	Asians	LC	64	26	23	67	IHC	Adjacent tissue	HCC tissues	8	Score =0
Lin et al	24	2010	China	Asians	HCC	132	10	68	74	IHC	Adjacent tissue	HCC tissues	8	10
Lin et al	24	2010	China	Asians	HCC	15	0	68	74	IHC	Normal tissue	HCC tissues	6	10
Che et al	25	2008	China	Asians	HCC	8	2	20	30	IHC	Normal tissue	HCC tissues	8	25
Fan et al	26	2008	China	Asians	HCC	52	23	29	46	IHC	Adjacent tissue	HCC tissues	8	5
Liu et al	27	2008	China	Asians	HCC	56	20	75	33	IHC	Adjacent tissue	HCC tissues	8	Score =0
Zhao et al	28	2006	China	Asians	LC	552	55	33	50	IHC	Normal tissue	HCC tissues	6	NR
Liang et al	29	2005	China	Asians	HCC	20	0	32	30	IHC	Normal tissue	HCC tissues	6	5
Liang et al	29	2005	China	Asians	HCC	62	0	32	30	IHC	Adjacent tissue	HCC tissues	8	5
Zheng and Chen	30	2005	China	Asians	HCC	12	0	20	30	IHC	Adjacent tissue	HCC tissues	8	Score =0
Song and Dou	31	2005	China	Asians	LC	10	0	29	41	IHC	Normal tissue	HCC tissues	6	Score =0
Song and Dou	31	2005	China	Asians	LC	10	0	29	41	IHC	Adjacent tissue	HCC tissues	8	Score =0
Nan et al	32	2005	China	Asians	HCC	10	0	19	28	IHC	Normal tissue	HCC tissues	6	5
Nan et al	32	2005	China	Asians	HCC	47	0	19	28	IHC	Adjacent tissue	HCC tissues	8	5
Zekri et al	33	2005	Egypt	Mixed	HCC	10	0	6	17	RT-PCR	Normal tissue	HCC tissues	6	NR
Xu and Yi	34	2004	China	Asians	PHC	10	0	26	20	IHC	Normal tissue	PHC tissues	6	5
Xu and Yi	34	2004	China	Asians	PHC	46	0	26	20	IHC	Adjacent tissue	PHC tissues	8	5
Zhao et al	35	2003	China	Asians	HCC	10	0	54	29	IHC	Normal tissue	HCC tissues	6	5
Zhao et al	35	2003	China	Asians	HCC	83	0	54	29	IHC	Adjacent tissue	HCC tissues	8	5
Yuan et al	36	2000	China	Asians	HCC	10	0	5	5	IHC	Adjacent tissue	HCC tissues	6	NR
						Control		Case
						U	M	U	M
Zekri et al	37	2014	Egypt	Mixed	HCC	11	2	10	21	MSP	Normal tissue	HCC tissues	6	NR
Zhang et al	38	2013	China	Asians	HCC	17	31	23	25	MSP	Normal tissue	HCC tissues	7	NR
Sun et al	39	2006	China	Asians	HCC	12	2	13	32	MSP	Normal tissue	HCC tissues	6	NR

Abbreviations: HCC, hepatocellular carcinoma; IHC, immunohistochemical; LC, liver cancer; M, methylation; MSP, methylmion-specific PCR; NOS, quality assessment scale; NR, not reported; PHC, primary hepatic carcinoma; U, unmethylation; RT-PCR, reverse transcription polymerase chain reaction.

Figure 2 Forest plot of the relationship between FHIT expression and liver cancer risk. Note: Weights are from random effects analysis.

Abbreviations: CI, confidence interval; FHIT, fragile histidine triad protein; RR, relative risk.

Figure 3 Forest plot of the association between FHIT expression and TNM-stage of liver cancer.

Abbreviations: CI, confidence interval; FHIT, fragile histidine triad protein; RR, relative risk.

Figure 4 Forest plot of the association between FHIT expression and liver tumor size.

Abbreviations: CI, confidence interval; FHIT, fragile histidine triad protein; RR, relative risk.

Figure 5 Forest plot of the association between FHIT expression and merging liver cirrhosis into liver cancer.

Abbreviations: CI, confidence interval; FHIT, fragile histidine triad protein; RR, relative risk.

Table 2 Meta-analysis of the associations of FHIT expression and FHIT gene hypermethylation with liver cancer pathogenesis

Clinical features	RR (95% CI)	P-value	Heterogeneity test		Studies (n)	Model	Publication bias
			I^2 (%)	P-value			Begg’s test (P)	Egger’s test (P)
FHIT expression (adjacent vs cancer)	1.88 (1.58–2.25)	<0.05	79.80	0	11	Random effects analysis	0.09	0.06
FHIT expression (normal vs cancer)	2 (1.72–2.32)	<0.05	58.10	0.014	9	Random effects analysis	0.25	0.1
Overall liver cancer risk	1.93 (1.72–2.17)	<0.05	72.70	0	20	Random effects analysis	0.02	0.006
TNM stage (I + II vs III + IV)	2.13 (1.72–2.64)	<0.05	0	0.69	7	Fixed effects model	0.76	0.33
HBsAg	1.28 (0.88–1.86)	.0.05	0	0.85	5	Fixed effects model	0.46	0.66
Tumor size (≤5 cm vs >5 cm)	1.67 (1.36–2.05)	<0.05	47.1	0.08	7	Fixed effects model	0.76	0.42
Liver capsule	0.95 (0.41–2.22)	>0.05	78.4	0.003	4	Random effects analysis	0.73	0.61
Damage from liver cirrhosis	1.34 (1.06–1.69)	<0.05	0	0.37	3	Fixed effects model	0.3	0.56
Portal venous tumor emboli	0.71 (0.34–1.50)	>0.05	63.5	0.04	4	Random effects analysis	0.31	0.11
FHIT hypermethylation (normal vs cancer)	2.33 (1.85–2.93)	<0.05	0.000	0.422	3	Fixed effects model	0.602	0.25

Abbreviations: CI, confidence interval; FHIT, fragile histidine triad protein; HBsAg, hepatitis B surface antigen; RR, relative risk.

Figure 6 Forest plot of the association between FHIT gene hypermethylation and liver cancer risk.

Abbreviations: CI, confidence interval; FHIT, fragile histidine triad protein; RR, relative risk.

Figure 7 Funnel plot assessing the association of FHIT expression with liver cancer risk.

Abbreviations: FHIT, fragile histidine triad protein; RR, relative risk; SE, standard error.

Figure 8 Funnel plot of trim and filling method assessing the association of FHIT expression with liver cancer risk.

Abbreviations: FHIT, fragile histidine triad protein; SE, standard error.