Association of hypoxia-inducible factor-1α (HIF1α) 1772C/T gene
polymorphism with susceptibility to renal cell carcinoma/prostate
cancer

In this study, we used a meta-analysis method to evaluate the relationship between hypoxia-inducible factor-1α (HIF1α) 1772C/T gene polymorphism (rs 11549465) and renal cell carcinoma (RCC)/prostate cancer risk. We searched for relevant studies (before March 1, 2019) on Cochrane Library, Embase, and PubMed. Studies meeting the inclusion criteria were recruited into this meta-analysis. The outcome of dichotomous data was showed in the way of odds ratios (OR), and 95% confidence intervals (CI) were also counted. In this investigation, there was no association between HIF1α 1772C/T gene polymorphism and susceptibility to RCC in Caucasians, Asians as well as overall populations. In addition, HIF1α 1772C/T gene polymorphism was not found to be relevant to the survival in RCC. Interestingly, the T allele was relevant to prostate cancer risk in all populations, but not in Caucasians and Asians. However, the TT genotype and the CC genotype were not related to prostate cancer susceptibility in Asian, Caucasian, and all populations. In conclusion, the T allele of the HIF1α 1772C/T gene polymorphism was related to prostate cancer risk in the overall populations.


Introduction
Renal cell carcinoma is one of the most common renal neoplasms, accounting for approximately 3.9% of new cancers, and its morbidity was also on the rise in the past two decades (Pan et al., 2018;Hu et al., 2017). Cancer prognosis is affected by the underlying tumor biology and also by the host inflammatory response to the disease (Chaves et al., 2018). Surgery and other treatments like conventional chemotherapy and radiotherapy are applied to RCC, but it still has the highest mortality and recurrence rate among the genitourinary carcinomas (Pan et al., 2018;Zhang et al., 2018;Zhao et al., 2018). Prostate cancer contributes the most to morbidity and mortality in men all over the world, while its morbidity has had a significant increase in recent years (Ramalho-Carvalho et al., 2018;Bernal-Ramos et al., 2017). In order to overcome the treatment resistance that occurs with recurrence, it is rather critical to developing more effective methods for early diagnosis and treatment for prostate cancer (Wang et al., 2018b). The current evidence suggests that genetic factors contribute to the risk of RCC and prostate cancer.
HIF1α, a member of the HIF transcription factor family, controls various cellular pathways involved in embryonic development and many normal physiological processes such as cell apoptosis, response to hypoxia chemotaxis, and proliferation. HIF1α is also essential for cell survival, energy metabolism, angiogenesis, progression, and metastasis of tumors (Maybin et al., 2018;Qian et al., 2018;Wang et al., 2018a;Wilkes et al., 2018). HIF1α 1772C/T (rs11549465) gene polymorphism increases the risk of certain cancers (Wang et al., 2018a;Kang et al., 2011;Anam et al., 2015;Li et al., 2015). However, some investigations revealed that the HIF1α 1772C/T (rs 11549465) gene polymorphism was not related to the risk of other cancers like hepatocellular carcinoma and colorectal cancer (Liu et al., 2014;Xu et al., 2014). The available evidence is insufficient to justify the divergence and sparse data in the reported studies. This meta-analysis was performed to assess whether the gene polymorphism of HIF1α 1772C/T (rs 11549465) is related to the susceptibility to RCC and prostate cancer.

Search strategy
We searched Cochrane Library, Embase, and PubMed (from inception to March 1, 2019) to identify eligible studies using the search terms "hypoxia-inducible factor-1α" or "HIF1α" and "renal cell carcinoma" or "renal cancer" or "RCC" or "prostate cancer".

Inclusion and exclusion criteria
Inclusion criteria: (1) the disease had to be renal cancer, prostate cancer; (2) two comparison groups (case group vs. control group) had to be included; (3) the detailed genotype distribution data should be provided. Exclusion criteria: (1) editorials, case reports, and review articles; (2) when the main results did not include HIF1α 1772C/T and outcome; (3) the effect of HIF1α gene levels on disease was investigated and (4) when detailed genotype distribution of HIF1α 1772C/T was not provided.

Data extraction and synthesis
From every eligible investigation, we extracted the important information, which was the first author's surname, publication year, and number of patients with RCC, prostate cancer and control patients for HIF1α 1772C/T genotypes. The frequency of HIF1α 1772C/T in each control and case group was counted in accordance with the corresponding genotype distribution. Survival data of renal cell or prostate cancer was also extracted.

Statistical analysis
Each statistical analysis was conducted by means of the Cochrane Review Manager Version 5 (Cochrane Library, UK). The calculated statistics were summarized with the help of a fixed-effects model, but once the p-value of the heterogeneity test was under 0.1, a random-effects model (Der Simonian-Laird method) had to be used. The outcomes were expressed as the odds ratio (OR) of the binary data with 95% confidence intervals (CI). Statistical significance was found when the pooled OR had a P < 0.05. The heterogeneity test was tested by I 2 -value among included studies.

Results
Study characteristics for relationship between the HIF1α 1772C/T gene polymorphism and susceptibility to RCC In order to study the relationship between HIF1α 1772C/T gene polymorphism and RCC risk (Tab. 1), our metaanalysis recruited four studies (Clifford et al., 2001;Ollerenshaw et al., 2004;Morris et al., 2009;Qin et al., 2012), which contained 1160 case series and 1241 controls. And the relevant data was extracted by the first author's

Study characteristics for relationship between HIF1α 1772C/T gene polymorphism and susceptibility to prostate cancer
Six studies (Orr-Urtreger et al., 2007;Li et al., 2007Li et al., , 2012Foley et al., 2009;Fraga et al., 2014;Chau et al., 2005) including 3150 case series and 3370 controls were included in our research to find the relationship between HIF1α 1772C/T gene polymorphism and the prostate cancer risk (Tab. 1).

Study characteristics for the relationship between the HIF1α 1772C/T gene polymorphism and the RCC survival
Two studies Ferreira et al., 2017) were recruited into our research to find the association of the HIF1α 1772C/T gene polymorphism with the RCC survival.
Association of the HIF1α 1772C/T gene polymorphism with the survival of RCC HIF1α 1772C/T gene polymorphism is not related to RCC survival in the overall population (T: OR = 0.88, 95% CI:

Discussion
In this study, we investigated the relationship between the HIF1α 1772C/T gene polymorphism (rs 11549465) and susceptibility to RCC/prostate cancer. We did not find a relationship between HIF1α 1772C/T gene polymorphism and RCC susceptibility or survival for the overall population, neither for Caucasians nor Asian populations individually. It was interesting to find that the T allele was related to prostate cancer risk in overall populations, but not in Caucasians and Asian populations. However, the TT and CC genotypes had no relationship with prostate cancer susceptibility in the whole populations, Asians, and Caucasians. There were some other meta-analyses in previous papers from this group. Li et al. (2015) completed a meta-analysis on the association of HIF1α 1772C/T gene polymorphism with cancer risk, reporting that HIF1α 1772C/T gene polymorphism is not associated with susceptibility to renal cell carcinoma/prostate cancer. Li et al. (2013) made a metaanalysis reporting that HIF1α 1772C/T gene polymorphism was not either associated with susceptibility to renal cell carcinoma/prostate cancer. Anam et al. (2015) reported that the HIF1α 1772C/T gene polymorphism was not related to susceptibility to RCC/prostate cancer by means of a metaanalysis containing genome-wide association studies of HIF1α 1772C/T polymorphism with cancer risk. These meta-analyses mentioned above were not performed by ethnicity. Our results revealed that the HIF1α 1772C/T gene polymorphism was not related to the RCC risk among Caucasians, Asians, and overall populations. Additionally, there was no association between the HIF1α 1772C/T gene polymorphism and survival in RCC. Interestingly, the T allele was related to the risk of prostate cancer among all populations, but not among Caucasians and Asian populations. However, the TT genotype and the CC genotype were not related to prostate cancer susceptibility among Asians, Caucasians, and overall populations. These results add new information inferred by our further analysis considering the different ethnic groups.

Conclusion
This meta-analysis suggests that the T allele was related to the risk of prostate cancer in the overall populations, but not in Caucasians and Asians. However, additional correlation research is needed to further confirm their association.
Funding Statement: This study was supported by the Guangzhou Medical Key Discipline Construction Project (2017-2019) and the Science and Technology Project of Shantou (Shanfuke (2019) 106-4: 190606165268433).

Conflicts of Interest:
The authors declare that they have no conflicts of interest to report regarding the present study.
Availability of Data and Materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' Contributions: TBZ was in charge of conceiving and designing the study. TBZ, CLL and HYL were responsible for the collection of data and performing the statistical analysis and manuscript preparation. CLL and WJW were responsible for checking the data. All authors were responsible for drafting the manuscript, reading it, and approving the final version.