Sun X, Liu YD, Gao W, Shen SH, Li M. HIF-1α -1790G>A polymorphism significantly increases the risk of digestive tract cancer: A meta-analysis. World J Gastroenterol 2015; 21(5): 1641-1649 [PMID: 25663785 DOI: 10.3748/wjg.v21.i5.1641]
Corresponding Author of This Article
Ying-Di Liu, MD, PhD, Department of Gastroenterology, Hainan Branch of PLA General Hospital, Haitangwan, Sanya 572000, Hainan Province, China. liuyingti@yeah.net
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Meta-Analysis
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Xiao Sun, Wei Gao, Shao-Hua Shen, Meng Li, Department of Gastroenterology of PLA General Hospital, Beijing 100853, China
Ying-Di Liu, Department of Gastroenterology, Hainan Branch of PLA General Hospital, Sanya 572000, Hainan Province, China
ORCID number: $[AuthorORCIDs]
Author contributions: Sun X, Liu YD and Gao W designed the study, analyzed the data and wrote the manuscript; Shen SH and Li M contributed to the databases searches, the selection of studies and discussions; Liu YD designed the study, contributed to the discussion and edited the manuscript as the corresponding author.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ying-Di Liu, MD, PhD, Department of Gastroenterology, Hainan Branch of PLA General Hospital, Haitangwan, Sanya 572000, Hainan Province, China. liuyingti@yeah.net
Telephone: +86-751-38831528 Fax: +86-898-38853390
Received: June 26, 2014 Peer-review started: June 27, 2014 First decision: August 15, 2014 Revised: August 27, 2014 Accepted: September 30, 2014 Article in press: September 30, 2014 Published online: February 7, 2015
Abstract
AIM: To investigate the association between hypoxia-inducible factor-1α (HIF-1α) polymorphisms (-1772C>T and -1790G>A) and the risk of digestive tract cancer.
METHODS: A total of 13 eligible studies were retrieved from PubMed, EMBASE, and the China National Knowledge Infrastructure database. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of the associations.
RESULTS: By pooling the eligible studies, we found that the HIF-1α -1772C>T polymorphism was not associated with the risk of developing digestive tract cancer (dominant comparison, OR: 1.156; 95%CI: 0.839-1.593; Pheterogeneity = 0.007), and no significant association was found in the Asian population or the Caucasian population. However, for the -1790G>A polymorphism, carriers of the variant -1790A allele had a significantly increased risk of digestive tract cancer compared with those with the wildtype -1790G allele (dominant comparison, OR: 3.252; 95%CI: 1.661-6.368; Pheterogeneity < 0.001). Additionally, this increased risk of digestive cancer was only detected in Asians; there was no significant association in Caucasians.
CONCLUSION: This meta-analysis demonstrates that the HIF-1α -1790G>A polymorphism is associated with a significantly increased risk of digestive tract cancer, while the -1772C>T polymorphism is not.
Core tip: The functional polymorphisms of hypoxia-inducible factor-1α (HIF-1α) (-1772C>T and -1790G>A) have been extensively investigated; however, the relationship between HIF-1α polymorphisms and digestive tract cancer has remained unclear. In this work, we found that the HIF-1α -1772C>T polymorphism was not associated with the overall risk of developing digestive tract cancer (dominant comparison, OR: 1.156; 95%CI: 0.839-1.593; Pheterogeneity = 0.007). However, the variant -1790A allele significantly increased the risk of digestive tract cancer (OR: 3.252; 95%CI: 1.661-6.368; Pheterogeneity < 0.001).
Citation: Sun X, Liu YD, Gao W, Shen SH, Li M. HIF-1α -1790G>A polymorphism significantly increases the risk of digestive tract cancer: A meta-analysis. World J Gastroenterol 2015; 21(5): 1641-1649
Genetic polymorphisms are natural DNA sequence variations that occur in the healthy population with an expected frequency higher than 1%[1]. Common genetic polymorphisms include single nucleotide polymorphisms, insertions, deletions, minisatellites and microsatellites. Approximately 90% of DNA polymorphisms are single nucleotide polymorphisms (SNPs). Functional SNPs in gene regulatory or coding sequences can alter gene expression or affect the function of proteins. SNPs are associated with inter-individual variation and diversity and have recently been considered as principal genetic elements involved in the development of complex diseases, such as cancer[2].
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor complex that activates gene transcription, enhancing oxygen availability and allowing metabolic adaptation to hypoxia[3]. HIF-1 is composed of two subunits, HIF-1α and HIF-1β. HIF-1α plays a critical role in adjusting oxygen levels, and it is involved in the processes of angiogenesis[4-6] and cell proliferation[7,8]. HIF-1α is expressed in many cancer cells as a result of oncogene expression and intratumoral hypoxia[9,10]. Furthermore, it has been demonstrated that HIF-1α is an unfavorable prognostic factor in a variety of digestive tract cancers, such as pancreatic cancer and hepatocellular carcinoma[11-13].
The HIF-1α gene is located on chromosome 14q21-24. Two common SNPs in the protein coding region of the HIF-1α gene have been widely investigated: the C-to-T substitution at -1772 (-1772C>T, P582S, or rs11549465) and the G-to-A substitution at -1790 (-1790G>A, A588T, or rs11549467). The -1772C>T polymorphism leads to a proline-to-serine substitution, and the -1790G>A polymorphism leads to an alanine-to-threonine substitution. Both the -1772C>T and -1790G>A polymorphisms are functional and located in the oxygen-dependent degradation domain, which is closely related to the N-terminal transactivation domain of HIF-1α[4,14]. Therefore, these functional SNPs may affect the stability and trans-activating capacity of HIF-1α. Additionally, evidence also suggests that these functional SNPs could alter the susceptibility to various types of cancer. However, current studies have yielded conflicting results about HIF-1α polymorphisms and the risk of developing cancer of the digestive tract. For example, Kang et al[15] found that the -1772C>T polymorphism was associated with an increased risk of colorectal cancer; however, Li et al[16] did not find any significant association with gastric cancer risk. Thus, this meta-analysis was performed to ascertain the relationship between the HIF-1α -1772C>T and -1790G>A polymorphisms and susceptibility to cancer of the digestive tract.
MATERIALS AND METHODS
Selection of eligible studies
The eligible studies were obtained by searching online databases. In order to identify as many related articles as possible, PubMed, EMBASE, and the China National Knowledge Infrastructure (CNKI) were searched. Combinations of medical subheadings and the key words “HIF-1α” or “hypoxia-inducible factor 1, α subunit” or “HIF1A” or “HIF-1α”, “polymorphism, single nucleotide” or “single nucleotide polymorphism” or “polymorphism” or “SNP”, and “neoplasms” or “cancer” or “tumor” were used to search the databases. Alternative spellings of these key words were also considered. The most recent research was performed on July 15, 2013, and there was no limitation on the research.
Inclusion and exclusion criteria
Studies were selected according to the following inclusion criteria: (1) case-control studies; (2) investigation of the association of HIF-1α polymorphisms (-1772C>T and -1790G>A) and the risk of developing digestive tract cancer; (3) cancer diagnosis by histopathology; and (4) studies providing detailed genotype frequencies. Studies without detailed genotype frequencies were excluded. The titles and abstracts of the records retrieved from the databases were screened, and the full-text papers were further evaluated to confirm eligibility. Two reviewers (Sun X and Liu YD) extracted the eligible studies independently according to the inclusion criteria. Disagreements between the two reviewers were discussed with another reviewer until a consensus was achieved.
Data extraction
Data from the eligible studies were independently extracted by the two reviewers using a predesigned data collection form. The following data were collected: name of first author, year of publication, country where the study was carried out, ethnicity, cancer types, the source of the controls, number of cases and controls, genotype frequency in the cases and controls. Ethnicity was categorized as Asian, Caucasian, or Latin American (Table 1). According to the source of control, the eligible studies were defined as hospital-based (HB) and population-based (PB). The sample size in the eligible studies was classified as either large (> 500) or small (< 500). Hardy-Weinberg equilibrium (HWE) in the controls was tested using the χ2 test for goodness of fit, and P < 0.05 was considered as the absence of HWE. Two reviewers reached consensus on each item.
Table 1 Baseline characteristics of eligible studies.
The strength of the association between the HIF-1α -1772C>T and -1790G>A polymorphisms and the risk of developing digestive tract cancer was measured by odds ratios (ORs) with 95% confidence intervals (CIs). The estimates of the pooled ORs were obtained by calculating a weighted average of the ORs from each study. A 95%CI was used for the test of statistical significance, and a 95%CI without an OR of 1 indicated a significantly increased or reduced cancer risk. The pooled ORs were calculated for allele comparison (A vs a), heterozygote comparison (Aa vs aa), and dominance modeling (AA/Aa vs aa) (A: the mutant allele, a: the wildtype allele; the -1772T and -1790A alleles were considered as mutant alleles). The combined genotype was reported by Kang et al[15] and Knechtel et al[17]; thus, only dominant comparison models were calculated for these 2 studies. Subgroup analyses were also conducted according to ethnicity, cancer type, source of control, and sample size. A sub-group analysis was not performed for subgroups containing less than 2 studies. Sensitivity analyses were performed to identify each individual study’s effect on the pooled results and test the reliability of the results.
The χ2 test based on Q was used to check the statistical heterogeneity between studies, and the heterogeneity was considered significant when P < 0.10. The fixed-effects model (based on the Mantel-Haenszel method) and random-effects model (based on the DerSimonian-Laird method) were used to pool the data from different studies. The fixed-effects model was used when there was no significant heterogeneity; otherwise, the random-effects model was applied[18]. Meta-regression was performed to detect the source of heterogeneity. Publication bias was detected by Begg’s funnel plot and Egger’s linear regression test, and a P < 0.05 was considered significant[19]. To test the influence of publication bias, the fail-safe number was also calculated for P = 0.05 (Nfs0.05) and P = 0.01 (Nfs0.01)[20]. All statistical analyses were calculated with STATA software version 10.0 (Stata Corp., College Station, TX, USA), and all P values are two-sided.
RESULTS
Overview of eligible studies
According to our search strategy, 558 records were retrieved and screened. After primary screening, 16 full-text papers were retrieved for further assessment of eligibility. Finally, 13[15-17,21-30] eligible studies were included and 3 studies were excluded because they were not related to cancer risk[31,32] or the HIF-1α -1772C>T and -1790G>A polymorphisms[33]. The procedure for study selection is shown in Figure 1.
Of the 13 eligible studies, 2182 cancer patients and 3101 controls were enrolled. The baseline characteristics of the included studies are shown in Table 1. Six types of digestive tract cancer were investigated: oral cancer, esophageal cancer, gastric cancer, pancreatic cancer, hepatocellular carcinoma, and colorectal cancer. Most studies were carried out among Asian and Caucasian populations, while only one study was performed in Latin America. The -1772C>T polymorphism was investigated in all studies, and the -1790G>A polymorphism was studied in 10 studies[16,17,21-28]. For the -1772C>T polymorphism, the absence of HWE in controls was detected in 3 studies[21,22,27]; however, no disequilibrium was detected for the -1790G>A polymorphism. In the control population, homozygotes for the variant -1772TT were detected in 4 studies[20,23,26,27], while the -1790AA genotype was not detected among the cancer cases.
Meta-analysis results
-1772C>T polymorphism: By pooling all the eligible studies, we found that the -1772C>T polymorphism was not associated with the risk of digestive tract cancer in any of the three comparison models (dominant comparison, OR: 1.156; 95%CI: 0.839-1.593; Pheterogeneity = 0.007; Figure 2). The meta-analysis results for the -1772C>T polymorphism are shown in Table 2. Sub-group analyses were performed, and no significant association with the risk of digestive tract cancer was found among Asians or Caucasians in the HB studies. Because the data from 3 studies were not inconsistent with HWE, we performed sub-group analyses according to HWE, and no statistical association was found in any of the groups. In terms of cancer types, we found that only the variant -1772T allele was associated with a significantly increased risk of pancreatic cancer (OR: 1.753; 95%CI: 1.225-2.508; Pheterogeneity = 0.349), while no significant association was observed with oral cancer or colorectal cancer. Notably, sample size had a significant influence on the pooled results. As shown in Table 2, large studies suggested an increased risk, while small studies revealed no significant association.
Table 2 Meta-analysis results of -1772C>T polymorphism.
Figure 2 Forrest plot of the -1772C>T polymorphism and the risk of digestive tract cancer.1Weights are from random effects analysis. Dominant comparison: TT + CT vs CC. OR: Odds ratio.
Begg’s funnel plot (P = 0.373; Figure 3) and Egger’s linear regression test (P = 0.813) suggested that no publication bias affected the results. A sensitivity analysis also confirmed the stability of our results because no individual study affected the pooled results significantly (Figure 4). Due to the significant heterogeneity among the studies, a meta-regression was performed to identify the source of heterogeneity (for the dominant model), and the results suggested that ethnicity (P = 0.021), sample size (P = 0.002), and HWE (P < 0.001) were the sources of heterogeneity between the studies.
Figure 4 Meta-analysis estimates, with given named study omitted (A, B).
-1790G>A polymorphism: The results of the meta-analysis of the -1790G>A polymorphism are shown in Table 3. A pooled analysis of the 10 eligible studies revealed that the variant -1790A allele significantly increased the risk of digestive tract cancer, as observed in the dominant model (OR: 3.252; 95%CI: 1.661-6.368; Pheterogeneity < 0.001; Figure 5), the allele comparison (OR: 4.455; 95% CI: 1.938-10.241; Pheterogeneity < 0.001), and the heterozygote comparison. Next, stratified analyses were performed. As shown in Table 3, the source of controls and the sample size did have a significant effect on the results. However, we only found a significantly increased risk in Asians, not in Caucasians. In Asians, the -1790G>A polymorphism was associated with increased susceptibility to cancers of the digestive tract, while no significant association was observed in Caucasians. As for the cancer types, the -1790G>A polymorphism increased the risk of oral cancer and pancreatic cancer, but not the risk of colorectal cancer (Table 3).
Table 3 Meta-analysis results of -1790G>A polymorphism.
Figure 5 Forrest plot of the -1790G>A polymorphism and the risk of digestive tract cancer.1Weights are from random effects analysis. Dominant comparison: AA + GA vs GG.
The results of Begg’s test (P = 0.05) and Egger’s test (P = 0.064) indicated the presence of significant publication bias. Additionally, the stability of our results was confirmed by the sensitivity analysis (Figure 4B). The fail-safe number was calculated to estimate the influence of publication bias. The value of the fail-safe number was large (Nfs0.05 = 359.34, Nfs0.01 = 172.98), which suggested that the publication bias was low and our result was reliable. Due to the significant heterogeneity among the studies, a meta-regression was performed to identify the source of the heterogeneity (for the dominant model). The results suggested that sample size (P = 0.002) and HWE (P < 0.001) were the sources of heterogeneity between studies.
DISCUSSION
The results of the present meta-analysis suggest that the -1772C>T polymorphism of the HIF-1α gene is not associated with the risk of digestive tract cancer; however, the -1790G>A polymorphism significantly increases the susceptibility to digestive tract cancer.
HIF-1α is a critical gene involved in the cellular response to hypoxia. By activation of various genes that are related to the regulation of angiogenesis, cell survival, apoptosis, and the proliferative response, HIF-1α has an important role in tumor progression and metastasis[34,35]. In the presence of oxygen, HIF-1α is hydroxylated and degraded by the proteasome[36]; however, in a hypnotic microenvironment, the HIF-1α protein accumulates[37]. Studies have shown that HIF-1α is overexpressed in various digestive tract tumors, such as colon cancer, pancreatic cancer, stomach cancer, and esophageal cancer[9,38]. The functional -1772C>T and -1790G>A polymorphisms of HIF-1α are associated with an increased trans-activation capacity of HIF-1α under normoxic and hypoxic conditions[4]. Thus, these two SNPs may alter the risk of digestive tract cancer.
In this meta-analysis, we identified 13 eligible studies[15-17,21-30] and found that the -1772C>T polymorphism was not associated with the risk of digestive tract cancer. Stratified analyses according to ethnicity, source of controls, and HWE did not find any differences between the sub-groups. The results suggested that the -1772C>T did not alter the overall risk of developing digestive tract cancer. However, the results of this meta-analysis did reveal that the -1790G>A polymorphism was associated with a significantly increased risk of digestive tract cancer, and an elevated susceptibility to cancer was also observed in the majority of the sub-groups. Specifically, we found that Asian carriers of the variant -1790A allele had an increased risk compared with Caucasians. The difference between ethnicities may be explained by differences in the genetic background, lifestyle, and environmental exposure between the groups[39]. Additionally, the -1772C>T and -1790G>A polymorphisms had different impacts on the risk of developing a specific kind of cancer (Table 2 and Table 3), suggesting that HIF-1α polymorphisms may exert cancer type-specific effects.
Notably, significant heterogeneity was detected in this meta-analysis. Meta-regression and subgroup analyses were carried out to detect the source of this heterogeneity. For both -1772C>T and -1790G>A, ethnicity was the source of the heterogeneity. For -1772C>T, sample size and HWE also contributed to the observed heterogeneity. On the other hand, the sensitivity analysis confirmed the reliability and stability of our results. Additionally, no evidence of significant publication bias was not found by Egger’s test or Begg’s test.
While we were conducting this meta-analysis, an updated meta-analysis of HIF-1α polymorphisms was published[40]. Compared with the updated meta-analysis, we focused exclusively on digestive tract cancer and included more eligible studies related to this type of cancer; Liu and Zhang[40] only included studies before 2011. Because more eligible studies were included in our meta-analysis, we performed comprehensive sub-group analyses according to cancer type, sample size, HWE, and ethnicity. However, limitations of our meta-analysis should also be noted. First, although we performed a comprehensive meta-analysis, the number of relevant studies was limited and we could not perform sub-group analyses for each kind of digestive tract cancer. Second, the sample sizes in the included studies were relatively small. For the -1772C>T polymorphism, increased susceptibility was observed in large studies, while no significant association was found in small studies. Third, the genotype distribution of the controls was not in agreement with HWE in 3 studies on the -1772C>T polymorphism, although sub-group analysis demonstrated that the absence of HWE had no significant effect on the pooled results.
In summary, in this meta-analysis of 13 eligible studies, we found that the -1790G>A polymorphism of HIF-1α significantly increases the susceptibility to digestive tract cancer, while the -1772C>T polymorphism is not associated with significant risk. Further studies with larger sample sizes are warranted to validate these associations, particularly for the -1772C>T polymorphism.
COMMENTS
Background
Hypoxia-inducible factor-1α (HIF-1α) is a critical regulator of oxygen levels, and it is involved in the process of angiogenesis. The C-to-T substitution at -1772 (-1772C>T, rs11549465) and the G-to-A substitution at -1790 (-1790G>A, rs11549467) are two common single nucleotide polymorphisms of HIF-1α.
Research frontiers
Previous association studies have reported the association between HIF-1 polymorphisms and the risk of digestive tract cancer. However, these studies have reported conflicting results, and the sample size was small in the majority of these studies. Therefore, we conducted this meta-analysis to address this issue.
Innovations and breakthroughs
Based on this meta-analysis, the HIF-1α -1772C>T polymorphism was not associated with the overall risk of digestive tract cancer [odds ratio (OR): 1.156; 95%CI: 0.839-1.593]. However, the -1790G>A polymorphism significantly increased the risk of digestive tract cancer (OR: 3.252; 95% CI: 1.661-6.368).
Applications
These results highlighted that HIF-1α -1790G>A plays a role in digestive tract cancer, indicating that this point mutation may affect the transcription of HIF-1α. Further exploration of the mechanism will improve our understanding of the role and function of HIF-1α -1790G>A.
Terminology
Genetic polymorphisms are natural DNA sequence variations that can occur in the healthy population. Functional polymorphisms in gene regulatory or coding sequences may alter gene expression or the function of the encoded proteins. The -1790G>A polymorphism leads to an alanine-to-threonine substitution in the oxygen-dependent degradation domain, which is critical for the function of HIF-1α.
Peer-review
The Authors investigated the association of HIF-1α polymorphisms and risk of digestive cancer. The meta-analysis of 13 studies showed that HIF-1α -1790G>A polymorphism is associated with a significantly increased risk of digestive tract cancer.
Footnotes
P- Reviewer: Sperti C, Sakata N S- Editor: Qi Y L- Editor: Cant MR E- Editor: Wang CH
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