The Clinicopathologic and Prognostic Value of Hypoxia-Inducible Factor-2α in Cancer Patients: A Systematic Review and Meta-Analysis

Deqing Luo; Hui Liu; Dasheng Lin; Kejian Lian; Hongyue Ren

doi:10.1158/1055-9965.EPI-18-0881

DOI: 10.1158/1055-9965.EPI-18-0881 Published May 2019

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Figure 1.
Flowchart of the study selection process.
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Figure 2.
Forest plot of meta-analysis of OS on univariate analysis in association with HIF2α expression.
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Figure 3.
Forest plot of meta-analysis of OS on multivariate analysis in association with HIF2α expression.
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Figure 4.
Begg funnel plot of the effect of HIF2α expression on OS with univariate analysis (A) and multivariate (B) analysis.

Table 1.

Main characteristics of the studies included in the meta-analysis

Study	Year	Region	Histologic type	Expression	Case (n)	HIF2α⁺ (n)	HIF2α⁺ (%)	Analysis	Follow-up (months)	NOS Score	Quality
Bangoura G	2007	Asian	HCC	Protein	315	219	69.5	UA/MA	85	6	High
Biswas S	2012	Non-Asian	RCC	Protein	112	46	41.1	UA/MA	180	6	High
Chen CB	2011	Asian	Chondrosarcoma	Protein	34	18	52.9	UA/MA	98	8	High
Cleven A	2007	Non-Asian	CRC	Protein	133	43	32.3	UA/MA	150	7	High
Gao ZJ	2017	Asian	Lung cancer	Protein	140	64	45.7	UA	100	5	High
Griffiths EA	2008	Non-Asian	Gastric and esophageal cancers	Protein	172	106	61.6	UA	118	7	High
Holmquist-Mengelbier L	2006	Non-Asian	Neuroblastoma	Protein	72	23	31.9	UA	90	4	Low
Jubb AM	2009	Non-Asian	Colon cancer	Protein	159	85	53.5	UA/MA	140	7	High
Koukourakis MI	2006	Non-Asian	HNSCC	Protein	198	116	58.6	UA/MA	90	4	Low
Leek RD	2002	Non-Asian	Breast cancer	Protein	139	45	32.4	MA	126	7	High
Li W	2016	Asian	Osteosarcoma	mRNA	82	42	51.2	MA	136	8	High
Li WZ	2017	Asian	PDAC	Protein	283	148	52.3	UA/MA	62	6	High
Lim E	2017	Asian	OSCC	Protein	56	23	41.1	UA	60	4	Low
Liu YZ	2009	Asian	RCC	Protein	60	38	63.3	UA/MA	72	4	Low
Luan YJ	2013	Asian	Lung cancer	Protein	45	11	24.4	UA/MA	69	7	High
Pan TT	2015	Asian	HCC	Protein	90	69	76.7	UA/MA	66	8	High
Qu HX	2016	Asian	Neuroblastoma	Protein	30	15	50.0	UA	50	4	Low
ROH JL	2008	Asian	SDC	Protein	21	7	33.3	UA	120	4	Low
Sandlund J	2009	Non-Asian	RCC	mRNA	168	NR	NR	MA	247	3	Low
Sathornsumetee S	2008	Non-Asian	Malignant astrocytoma	Protein	45	NR	NR	MA	100	4	Low
Sivridis E	2002	Non-Asian	Endometrial carcinoma	Protein	81	14	17.3	UA	182	5	High
Sun HX	2010	Asian	HCC	Protein	254	122	48.0	UA/MA	60	6	High
Szendroi A	2016	Non-Asian	RCC	mRNA	69	36	52.2	UA	120	4	Low
Tong WW	2015	Asian	Gastric carcinoma	Protein	127	69	54.3	UA	60	5	High
Wang XC	2011	Asian	HCC	Protein	104	72	69.2	UA/MA	62	4	Low
Wang HX	2014	Asian	Breast cancer	Protein	102	62	60.8	UA/MA	50	5	High
Wang Q	2014	Asian	Epithelial ovarian cancer	Protein	40	32	80.0	UA	30	3	Low
Wei LF	2011	Asian	Lung cancer	Protein	51	37	72.5	UA	80	4	Low
Winter SC	2006	Non-Asian	HNSCC	Protein	139	21	15.1	UA/MA	100	6	High
Xie M	2015	Asian	RCC	Protein	86	NR	NR	UA/MA	20	3	Low
Yang SL	2014	Asian	HCC	Protein	126	17	13.5	UA	60	4	Low
Yang J	2017	Asian	Pancreatic cancer	Protein	70	47	67.1	UA/MA	25	6	High
Yao QY	2015	Asian	HCC	Protein	63	47	74.6	MA	62	4	Low
Yoshimura H	2004	Asian	CRC	Protein	87	26	29.9	UA	120	5	High
Yuan K	2009	Asian	Lung cancer	Protein	140	64	45.7	UA/MA	50	5	High
Yun F	2016	Asian	Lung cancer	Protein	112	53	47.3	UA/MA	65	4	Low
Zang L	2016	Asian	DLBCL	Protein	90	58	64.4	UA/MA	50	6	High
Zhang Q	2017	Asian	Pancreatic cancer	Protein	90	69	76.7	UA/MA	90	6	High
Zhou JC	2014	Asian	RCC	Protein	63	43	68.3	UA	150	4	Low
Zhu GQ	2010	Asian	OSCC	Protein	97	59	60.8	UA	60	5	High

Abbreviations: CRC, colorectal cancer; DLBCL, diffuse large B-cell lymphoma; HCC, hepatocellular cancer; HIF2α⁺: hypoxia-inducible factor-2α–positive expression; HNSCC, head and neck squamous cell cancer; MA, multivariate analysis; NOS, Newcastle–Ottawa scale; NR, not reported; OSCC, oral squamous cell carcinoma; PDAC, pancreatic ductal adenocarcinoma; RCC, renal cell cancer; SDC, salivary duct carcinoma; UA, univariate analysis.

Table 2.

Analysis for HIF2α and clinicopathologic features of patients with cancer

				Pooled data			Test for heterogeneity
Clinicopathologic features	Number of studies (n)	Number of cases (n)	Number of HIF2α⁺ (n)	RR	95% CI	P value	χ²	P value	I² (%)
Gender (male vs. female)	17	2,103	1,168	0.94	0.87–1.02	0.116	15.67	0.476	0
Differentiation (poor vs. well/moderate)	11	1,319	732	1.42	1.23–1.65	<0.001	22.77	0.012	56.1
TNM stage (III/VI vs. I/II)	10	1,241	693	1.50	1.35–1.66	<0.001	10.41	0.319	13.5
Lymph metastasis (yes vs. no)	9	961	525	1.38	1.24–1.54	<0.001	8.35	0.400	4.2

Abbreviations: HIF2α⁺, hypoxia-inducible factor-2α–positive expression; TNM stage, tumor–node–metastasis stage (designed by the American Joint Committee on Cancer).

Table 3.

Subgroup analysis for HIF2α and OS on univariate analysis in cancer patients

					Pooled data			Test for heterogeneity
Subgroups	Number of studies (n)	Case (n)	HIF2α⁺ (n)	HIF2α⁺ (%)	HR	95% CI	P value	P value	I² (%)
Region
Asian	26	2,713	1,442	53.2	1.75	1.44–2.11	<0.001	<0.001	61.9
Non-Asian	9	1,135	490	43.2	1.40	1.08–1.82	0.011	0.081	42.9
Histologic type
HCC	5	889	499	56.1	1.86	0.98–3.51	0.058	<0.001	88.5
Lung cancer	5	488	229	46.9	1.89	1.46–2.44	<0.001	0.348	10.2
RCC	5	390	163	41.8	0.91	0.58–1.48	0.703	0.020	65.8
CRC	3	379	154	40.6	1.72	1.21–2.43	0.002	0.536	0
Pancreatic cancer	3	443	264	59.6	1.97	1.42–2.75	<0.001	0.268	24
Gastric and esophageal cancers	2	299	175	58.5	1.65	1.21–2.26	0.002	0.776	0
HNSCC	2	337	137	40.7	1.79	1.26–2.53	0.001	0.927	0
Neuroblastoma	2	102	38	37.3	2.53	1.29–4.93	0.007	0.923	0
OSCC	2	153	82	53.6	1.14	0.73–1.80	0.567	0.638	0
Other^a	6	368	191	51.9	1.74	1.27–2.39	0.001	0.761	0
Case (n)
<100	19	1,232	625	50.7	1.77	1.35–2.33	<0.001	0.001	57.9
≥100	16	2,616	1,307	50.0	1.57	1.30–1.90	<0.001	0.001	61.2
Follow-up (months)
<100	24	2,672	1,441	53.9	1.80	1.48–2.20	<0.001	<0.001	63.3
≥100	11	1,176	491	41.8	1.36	1.10–1.67	0.004	0.165	29.5
Quality
High	21	2,760	1,420	51.4	1.70	1.40–2.07	<0.001	<0.001	62.7
Low	14	1,088	512	47.1	1.54	1.18–2.02	0.002	0.013	51.8

Abbreviations: CRC, colorectal cancer; HCC, hepatocellular cancer; HIF2α⁺, hypoxia-inducible factor-2α–positive expression; HNSCC, head and neck squamous cell cancer; OSCC, oral squamous cell carcinoma; RCC, renal cell cancer.
↵^a“Other” included chondrosarcoma, salivary duct carcinoma (SDC), endometrial carcinoma, breast cancer, epithelial ovarian cancer, and diffuse large B-cell lymphoma (DLBCL).

Table 4.

Subgroup analysis for HIF2α and OS on multivariate analysis in cancer patients

					Pooled data			Test for heterogeneity
Subgroups	Number of studies (n)	Case (n)	HIF2α⁺ (n)	HIF2α⁺ (%)	HR	95% CI	P value	P value	I² (%)
Region
Asian	17	2020	1,139	56.4	2.46	1.68–3.62	<0.001	<0.001	80.7
Non-Asian	8	1,093	356	32.6	1.72	1.40–2.12	<0.001	0.532	0
Histologic type
HCC	5	826	529	64.0	3.35	1.32–8.50	0.011	<0.001	91.6
RCC	4	426	84	19.7	1.19	0.56–2.50	0.654	0.012	72.4
Lung cancer	3	297	128	43.1	3.94	1.47–10.58	0.006	0.410	0
Pancreatic cancer	3	443	264	59.6	2.34	0.87–6.28	0.091	0.110	60.9
Breast cancer	2	241	107	44.4	1.78	1.19–2.67	0.005	0.280	14.2
CRC	2	292	128	43.8	2.78	1.23–6.31	0.014	0.177	45.2
HNSCC	2	337	137	40.7	1.85	1.10–3.11	0.021	0.161	45.2
Sarcomas^a	2	116	60	51.7	2.42	1.14–5.14	0.022	0.016	75.8
Other^b	2	135	58	43.0	2.45	1.28–4.66	0.007	0.378	0
Expression
Protein	23	2,863	1,453	50.8	2.23	1.69–2.93	<0.001	<0.001	74.0
mRNA	2	250	42	16.8	2.30	0.63–8.37	0.205	0.031	78.4
Case (n)
<100	11	755	399	52.8	2.63	1.75–3.96	<0.001	0.003	61.3
≥100	14	2,358	1,096	46.5	1.91	1.42–2.56	<0.001	<0.001	72.0
Follow-up (months)
<100	18	2,275	1,234	54.2	2.71	1.74–4.24	<0.001	0.003	63.1
≥100	7	838	261	31.1	1.90	1.44–2.51	<0.001	<0.001	69.9
Quality
High	17	2,277	1,169	51.3	2.28	1.71–3.05	<0.001	<0.001	63.5
Low	8	836	326	39.0	1.94	1.14–3.31	0.015	<0.001	83.9

Abbreviations: CRC, colorectal cancer; HCC, hepatocellular cancer; HIF2α⁺, hypoxia-inducible factor-2α–positive expression; HNSCC, head and neck squamous cell cancer; RCC, renal cell cancer.
↵^a“Sarcomas” included chondrosarcoma and osteosarcoma.
↵^b“Other” included malignant astrocytoma and diffuse large B-cell lymphoma (DLBCL).

Additional Files

Figures
Tables

Supplementary Data

Figure S1 - Forest plot of subgroup analysis on HIF-2Î± expression and the clinicopathological factors including gender (A), tumor differentiation (B), TNM stage (C) and lymph metastasis (D).
Figure S2 - Galbraith plot analysis of the effect of HIF-2Î± expression on OS with univariate analysis (A) and multivariate (B) analysis.
Figure S3 - (A) Forest plot of meta-analysis of OS on univariate analysis in association with HIF-2Î± expression after removing the studies by Biswas S, Sun HX, Szendroi A and Xie M. (B) Forest plot of meta-analysis of OS on multivariate analysis in association with HIF-2Î± expression after removing the studies by Sun HX, Wang XC, Xie M and Yao QY.
Figure S4 - Forest plot of subgroup analysis on HIF-2Î± expression and OS with univariate analysis including region (A), the number of case (B), the months of follow-up (C), quality of include study (D), and histological type (E).
Figure S5 - Forest plot of subgroup analysis on HIF-2Î± expression and OS with multivariate analysis including region (A), histological type (B), the expression type of HIF-2Î± (C), the number of case (D), the months of follow-up (E), and quality of include study (F).
Figure S6 - Sensitivity analysis among studies enrolled based on the OS with univariate analysis (A) and multivariate (B) analysis in cancer patients.
Table S1 - Clinicopathological characteristics of included studies in the meta-analysis