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Cancer Epidemiology, Biomarkers & Prevention
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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 and Hongyue Ren
Deqing Luo
1Department of Orthopaedic Surgery, The Affiliated Southeast Hospital of Xiamen University, Orthopaedic Center of People's Liberation Army, Zhangzhou, Fujian Province, China.
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Hui Liu
1Department of Orthopaedic Surgery, The Affiliated Southeast Hospital of Xiamen University, Orthopaedic Center of People's Liberation Army, Zhangzhou, Fujian Province, China.
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Dasheng Lin
1Department of Orthopaedic Surgery, The Affiliated Southeast Hospital of Xiamen University, Orthopaedic Center of People's Liberation Army, Zhangzhou, Fujian Province, China.
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Kejian Lian
1Department of Orthopaedic Surgery, The Affiliated Southeast Hospital of Xiamen University, Orthopaedic Center of People's Liberation Army, Zhangzhou, Fujian Province, China.
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Hongyue Ren
2Department of Pathology, The Affiliated Southeast Hospital of Xiamen University, Orthopaedic Center of People's Liberation Army, Zhangzhou, Fujian Province, China.
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  • For correspondence: hongyueren2012@163.com
DOI: 10.1158/1055-9965.EPI-18-0881 Published May 2019
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  • Figure 1.
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    Figure 1.

    Flowchart of the study selection process.

  • Figure 2.
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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.

  • Figure 4.
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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.

Tables

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  • Table 1.

    Main characteristics of the studies included in the meta-analysis

    StudyYearRegionHistologic typeExpressionCase (n)HIF2α+ (n)HIF2α+ (%)AnalysisFollow-up (months)NOS ScoreQuality
    Bangoura G2007AsianHCCProtein31521969.5UA/MA856High
    Biswas S2012Non-AsianRCCProtein1124641.1UA/MA1806High
    Chen CB2011AsianChondrosarcomaProtein341852.9UA/MA988High
    Cleven A2007Non-AsianCRCProtein1334332.3UA/MA1507High
    Gao ZJ2017AsianLung cancerProtein1406445.7UA1005High
    Griffiths EA2008Non-AsianGastric and esophageal cancersProtein17210661.6UA1187High
    Holmquist-Mengelbier L2006Non-AsianNeuroblastomaProtein722331.9UA904Low
    Jubb AM2009Non-AsianColon cancerProtein1598553.5UA/MA1407High
    Koukourakis MI2006Non-AsianHNSCCProtein19811658.6UA/MA904Low
    Leek RD2002Non-AsianBreast cancerProtein1394532.4MA1267High
    Li W2016AsianOsteosarcomamRNA824251.2MA1368High
    Li WZ2017AsianPDACProtein28314852.3UA/MA626High
    Lim E2017AsianOSCCProtein562341.1UA604Low
    Liu YZ2009AsianRCCProtein603863.3UA/MA724Low
    Luan YJ2013AsianLung cancerProtein451124.4UA/MA697High
    Pan TT2015AsianHCCProtein906976.7UA/MA668High
    Qu HX2016AsianNeuroblastomaProtein301550.0UA504Low
    ROH JL2008AsianSDCProtein21733.3UA1204Low
    Sandlund J2009Non-AsianRCCmRNA168NRNRMA2473Low
    Sathornsumetee S2008Non-AsianMalignant astrocytomaProtein45NRNRMA1004Low
    Sivridis E2002Non-AsianEndometrial carcinomaProtein811417.3UA1825High
    Sun HX2010AsianHCCProtein25412248.0UA/MA606High
    Szendroi A2016Non-AsianRCCmRNA693652.2UA1204Low
    Tong WW2015AsianGastric carcinomaProtein1276954.3UA605High
    Wang XC2011AsianHCCProtein1047269.2UA/MA624Low
    Wang HX2014AsianBreast cancerProtein1026260.8UA/MA505High
    Wang Q2014AsianEpithelial ovarian cancerProtein403280.0UA303Low
    Wei LF2011AsianLung cancerProtein513772.5UA804Low
    Winter SC2006Non-AsianHNSCCProtein1392115.1UA/MA1006High
    Xie M2015AsianRCCProtein86NRNRUA/MA203Low
    Yang SL2014AsianHCCProtein1261713.5UA604Low
    Yang J2017AsianPancreatic cancerProtein704767.1UA/MA256High
    Yao QY2015AsianHCCProtein634774.6MA624Low
    Yoshimura H2004AsianCRCProtein872629.9UA1205High
    Yuan K2009AsianLung cancerProtein1406445.7UA/MA505High
    Yun F2016AsianLung cancerProtein1125347.3UA/MA654Low
    Zang L2016AsianDLBCLProtein905864.4UA/MA506High
    Zhang Q2017AsianPancreatic cancerProtein906976.7UA/MA906High
    Zhou JC2014AsianRCCProtein634368.3UA1504Low
    Zhu GQ2010AsianOSCCProtein975960.8UA605High
    • 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 dataTest for heterogeneity
    Clinicopathologic featuresNumber of studies (n)Number of cases (n)Number of HIF2α+ (n)RR95% CIP valueχ2P valueI2 (%)
    Gender (male vs. female)172,1031,1680.940.87–1.020.11615.670.4760
    Differentiation (poor vs. well/moderate)111,3197321.421.23–1.65<0.00122.770.01256.1
    TNM stage (III/VI vs. I/II)101,2416931.501.35–1.66<0.00110.410.31913.5
    Lymph metastasis (yes vs. no)99615251.381.24–1.54<0.0018.350.4004.2
    • 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 dataTest for heterogeneity
    SubgroupsNumber of studies (n)Case (n)HIF2α+ (n)HIF2α+ (%)HR95% CIP valueP valueI2 (%)
    Region
     Asian262,7131,44253.21.751.44–2.11<0.001<0.00161.9
     Non-Asian91,13549043.21.401.08–1.820.0110.08142.9
    Histologic type
     HCC588949956.11.860.98–3.510.058<0.00188.5
     Lung cancer548822946.91.891.46–2.44<0.0010.34810.2
     RCC539016341.80.910.58–1.480.7030.02065.8
     CRC337915440.61.721.21–2.430.0020.5360
     Pancreatic cancer344326459.61.971.42–2.75<0.0010.26824
     Gastric and esophageal cancers229917558.51.651.21–2.260.0020.7760
     HNSCC233713740.71.791.26–2.530.0010.9270
     Neuroblastoma21023837.32.531.29–4.930.0070.9230
     OSCC21538253.61.140.73–1.800.5670.6380
     Othera636819151.91.741.27–2.390.0010.7610
    Case (n)
     <100191,23262550.71.771.35–2.33<0.0010.00157.9
     ≥100162,6161,30750.01.571.30–1.90<0.0010.00161.2
    Follow-up (months)
     <100242,6721,44153.91.801.48–2.20<0.001<0.00163.3
     ≥100111,17649141.81.361.10–1.670.0040.16529.5
    Quality
     High212,7601,42051.41.701.40–2.07<0.001<0.00162.7
     Low141,08851247.11.541.18–2.020.0020.01351.8
    • 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 dataTest for heterogeneity
    SubgroupsNumber of studies (n)Case (n)HIF2α+ (n)HIF2α+ (%)HR95% CIP valueP valueI2 (%)
    Region
     Asian1720201,13956.42.461.68–3.62<0.001<0.00180.7
     Non-Asian81,09335632.61.721.40–2.12<0.0010.5320
    Histologic type
     HCC582652964.03.351.32–8.500.011<0.00191.6
     RCC44268419.71.190.56–2.500.6540.01272.4
     Lung cancer329712843.13.941.47–10.580.0060.4100
     Pancreatic cancer344326459.62.340.87–6.280.0910.11060.9
     Breast cancer224110744.41.781.19–2.670.0050.28014.2
     CRC229212843.82.781.23–6.310.0140.17745.2
     HNSCC233713740.71.851.10–3.110.0210.16145.2
     Sarcomasa21166051.72.421.14–5.140.0220.01675.8
     Otherb21355843.02.451.28–4.660.0070.3780
    Expression
     Protein232,8631,45350.82.231.69–2.93<0.001<0.00174.0
     mRNA22504216.82.300.63–8.370.2050.03178.4
    Case (n)
     <1001175539952.82.631.75–3.96<0.0010.00361.3
     ≥100142,3581,09646.51.911.42–2.56<0.001<0.00172.0
    Follow-up (months)
     <100182,2751,23454.22.711.74–4.24<0.0010.00363.1
     ≥100783826131.11.901.44–2.51<0.001<0.00169.9
    Quality
     High172,2771,16951.32.281.71–3.05<0.001<0.00163.5
     Low883632639.01.941.14–3.310.015<0.00183.9
    • 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-2α 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-2α 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-2α 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-2α expression after removing the studies by Sun HX, Wang XC, Xie M and Yao QY.
    • Figure S4 - Forest plot of subgroup analysis on HIF-2α 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-2α expression and OS with multivariate analysis including region (A), histological type (B), the expression type of HIF-2α (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
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Cancer Epidemiology Biomarkers & Prevention: 28 (5)
May 2019
Volume 28, Issue 5
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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 and Hongyue Ren
Cancer Epidemiol Biomarkers Prev May 1 2019 (28) (5) 857-866; DOI: 10.1158/1055-9965.EPI-18-0881

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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 and Hongyue Ren
Cancer Epidemiol Biomarkers Prev May 1 2019 (28) (5) 857-866; DOI: 10.1158/1055-9965.EPI-18-0881
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