The authors have declared that no competing interests exist.
Conceived and designed the experiments: LJZ YBH. Performed the experiments: ZPC NNG. Analyzed the data: QZ YC BZ BS WJW ZPC NNG. Contributed reagents/materials/analysis tools: BS WJW ZPC. Wrote the paper: QZ YC BZ.
HIF-1α is a major regulator in tumor progression and metastasis which responds to hypoxia. Many studies have demonstrated that hypoxia-inducible factor1-α (HIF-1α) polymorphisms are significantly associated with cancer metastasis, but the results are inconsistent. We conducted a comprehensive meta-analysis to estimate the associations between HIF-1α C1772 T polymorphism and cancer metastasis.
Comprehensive searches were conducted on PubMed and EMBASE database. Fifteen studies were included in the meta-analysis. We used the OR and 95%CI to assess the associations between HIF-1α C1772T polymorphism and cancer metastasis. Heterogeneity and publication bias were also assessed by Q test,
Totally, fifteen studies including 1239 cases with metastasis-positive (M+) and 2711 cases with metastasis-negative (M−) were performed in this meta-analysis. The results showed that HIF-1a C1772T polymorphism was associated with the increased risk of cancer metastasis (T allele vs. C allele, OR = 1.36, 95% CI = 1.12–1.64; TT+ TC vs. CC, OR = 1.39, 95% CI = 1.13–1.71; TT vs. TC+ CC, OR = 1.93, 95% CI = 0.86–4.36). In the subgroup analyses, the significant associations remained significant among Asians, Caucasians and other cancers in the dominant model. Publication bias was not observed in the analysis.
Our results indicate that the HIF-1αC1772T polymorphism T allele may increase the risk of cancer metastasis, which might be a potential risk factor of cancer progress.
Cancer metastasis is a progress that tumor cells displace from the primary site to distance site where cancer cells adapt to a tissue microenvironment and is the most important cause of death in cancer patients
Genetic polymorphisms have been considered as the main genetic elements involved in the occurrence and development of cancer
The published case-control studies that investigated the associations between the HIF-1α C1772T polymorphism and cancer metastasis were searched on PubMed and EMBASE database (between January 1, 2005 and December 1, 2012). The keywords and terms used for this search were “HIF-1 OR hypoxia-inducible factor-1”, “polymorphism” AND “cancer”. In addition, references of retrieved publications were also screened by hand-searched. Studies included in the current meta-analysis have to meet the following inclusion criteria: (i) independent case-control design, (ii) evaluation of the associations between HIF-1α C1772T polymorphism and cancer metastasis, and (iii) provide available genotype frequency.
Two investigators independently extracted data. If the data was different, the third reviewer was asked to check until the data was right. For each eligible study, we collected the following information: first author's name, the year of publication, country of origin, cancer type, ethnicity of study population, the number of metastasis-positive (M+) and metastasis-negative (M−) cases and genotypes. The criteria of metastasis-positive (M+) and metastasis-negative (M−) depended on TNM
The strength of the association between HIF-1α C1772 T and cancer metastasis was measured by odds ratio (OR) and 95% confident interval (CI). The influence of study size of evaluated studies on the results was assessed by the Weight. The statistical significance of the pooled OR was determined using the Z-test (
Heterogeneity between studies was assessed by the χ2-based Q-test and
27 studies were obtained to evaluate the relationship between HIF-1α C1772 T and cancer metastasis. Twelve of them were excluded (8 studies were excluded for lacking of accurate staging, 4 studies without genotype data). Finally, 15 articles
Study | Year | Cancer type | Country | Ethnicity | Total | Genotypes | ||||||
M(+) | M(−) | M(+) | M(−) | |||||||||
CC | CT | TT | CC | CT | TT | |||||||
Apaydin | 2008 | Breast | Turkey | Caucasian | 75 | 27 | 58 | 17 | - | 21 | 6 | - |
Kim | 2008 | Breast | Korea | Asian | 48 | 42 | 45 | 3 | - | 36 | 6 | - |
Lee | 2008 | Breast | Korea | Asian | 336 | 642 | 298 | 37 | 1 | 583 | 54 | 5 |
Naidu | 2009 | Breast | Malaysia | Asian | 187 | 215 | 127 | 60 | - | 166 | 49 | - |
Knechtel | 2010 | Colorectal | Austria | Caucasian | 221 | 127 | 174 | 47 | - | 106 | 21 | - |
Kang | 2011 | Colorectal | Korea | Asian | 24 | 26 | 19 | 5 | - | 19 | 7 | - |
Ling | 2005 | ESCC |
China | Asian | 25 | 24 | 16 | 9 | - | 23 | 1 | - |
Orr-Urtreger | 2007 | Prostate | Israel | Caucasian | 3 | 371 | 2 | 1 | 0 | 262 | 96 | 13 |
Hsiao | 2010 | Hepatocellular | China | Asian | 5 | 97 | 5 | 0 | - | 89 | 8 | - |
Shieh | 2010 | OSCC |
China | Asian | 106 | 199 | 99 | 7 | - | 183 | 16 | - |
Wang | 2011 | Pancreatic | China | Asian | 127 | 136 | 98 | 29 | - | 111 | 25 | - |
Qin | 2012 | Renal cell | China | Asian | 26 | 594 | 25 | 1 | - | 547 | 47 | - |
Fraga | 2011 | UADTC |
Brazil | Caucasian | 26 | 26 | 6 | 18 | 2 | 15 | 11 | 0 |
Mera-Menendez | 2012 | Larynx | Spain | Caucasian | 12 | 106 | 6 | 1 | 5 | 79 | 17 | 10 |
Chai | 2010 | Cervical | China | Asian | 18 | 79 | 10 | 7 | 1 | 55 | 18 | 6 |
ESCC esophageal squamous cell carcinoma.
OSCC Oral squamous cell carcinoma.
UADTC upper aerodigestive tract cancer.
We assessed the associations between the HIF-1α C1772T polymorphism and cancer metastasis. Overall, when all the eligible studies were pooled into the meta-analysis, variant T allele significantly increased the risk of cancer metastasis, compared with the wild-type C allele (OR = 1.36, 95% CI = 1.12–1.64,
(A) C allele vs. T allele. (B) The dominant model. (C) The recessive model. A fixed-effects model was used. The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the weight (inverse of the variance). The diamond represents the summary OR and 95% CI.
Under the dominant model, subgroup analysis based on cancer type was performed, significant associations were not found in colorectal cancer and breast cancer, but a significant association in other cancer was observed. In the stratified analysis by ethnicity, significant associations were observed among Asians and in Caucasians (
N | M(+) | M(−) | OR(95%CI) | ||||
Total | 15 | 1239 | 2711 | 1.39 (1.13–1.71) | 0.002 | 0.27 | 16.8 |
Tumor site | |||||||
Breast |
4 | 646 | 926 | 1.31 (0.98–1.75) | 0.07 | 0.31 | 16.3 |
Colorectal |
2 | 245 | 153 | 1.23 (0.74–2.07) | 0.43 | 0.38 | 0 |
Other |
9 | 348 | 1632 | 1.62 (1.13–2.31) | 0.008 | 0.17 | 31.3 |
Ethnicity | |||||||
Asian | 10 | 902 | 2054 | 1.31 (1.03–1.66) | 0.025 | 0.28 | 18.2 |
Caucasian | 5 | 337 | 657 | 1.65 (1.08–2.52) | 0.02 | 0.3 | 18 |
Totally, no significant heterogeneity was observed among studies for the associations between HIF-1α C1772 T polymorphism and cancer metastasis in the pooled analysis and stratified analysis of dominant model. The fixed-effects model was performed in the meta-analysis. Any single study was not found to change the pooled OR qualitatively by sensitivity analysis indicated that this meta-analysis is stable.
Begg's funnel plot and Egger's test were performed to assess the publication bias of literatures. As shown in
Each point represents a separate study for the indicated association.
The meta-analysis investigates the associations between HIF-1α C1772 T polymorphism and cancer metastasis. We found that variant T allele significantly increased the risk of cancer metastasis.
Hypoxia-inducible factor1α (HIF-1α) is a transcription factor was first found as a regulator of renal production of erythropoietin (Epo)
HIF-1α is overexpressed in regional or distant metastases and is also expressed higher in preneoplastic and premalignant lesions, indicating that overexpression of HIF-1α can occur very early in carcinogenesis which may become a potential biomarker of predicting tumor progress
For the stratification analyses based on ethnicity and cancer types. There was an evidence to indicate that the HIF-1α C1772T polymorphism was significantly associated with increased risk of cancer metastasis among Asians and Caucasians only for dominant genetic model. However, no significant association was found between the C1772T polymorphism and cancer metastasis in colorectal cancer and breast cancer under dominant model. Further studies using larger sample size are needed to validate. Kuwai et al.
There are some limitations and potential bias that must be acknowledged in our meta-analysis. First, only published studies were included in our studies, many unpublished data have been ignored in the analysis. Therefore, potentially publication bias will be existed in our results, although the statistical data did not reflect it. Second, because of lacking of detailed analysis about age, gender, smoking, drinking and so on, those potential factors may influence our results. Third, the number of the included studies was not large enough. So the statistical power is weak to evaluate the association between HIF-1a polymorphisms and metastasis, especially in stratified analyses.
In summary, our meta-analysis reveal that the HIF-1α C1772T polymorphism can increase the risk of cancer metastasis. Although some results of the analysis are limited by the small number of studies. Our results suggest that the polymorphism is a potential risk factor. Large sample size and well-designed studies are needed to evaluate our finding.