Lung cancer (LC) has been regarded as one of the most common causes of cancer-related death worldwide over the past few decades, with an estimated 2.1 million new diagnoses of LC in 2018, accounting for 12% of the total increase in cancer cases (1). In recent years, the incidence of LC in China has been consistent with the global trend, showing a rapid increase, and LC has since become the main cause of cancer-related deaths in China (2). It is predicted that the mortality of LC in China is likely to increase by about 40% between 2015 and 2030 (3). Despite advances in early detection, the majority of LC patients are often diagnosed at a later stage, resulting in a 5-year overall survival rate of only 10% to 15%, according to statistics (4). The burden of LC on our society is increasing day by day and cannot be ignored. Various factors can predispose people to LC, with smoking being the most prevalent factor. In addition, other potential risk factors include gender, age, race, ethnicity, and especially single nucleotide polymorphisms (SNPs) (5, 6).

Cytochrome P450s (CYP), phase I drug metabolizing enzymes, encode 57 CYP proteins in the human genome and are responsible for the metabolism of numerous endogenous and xenobiotic compounds (7). The CYP4F2 gene, a member of the CYP450 superfamily, is an ω-hydroxylase that catalyzes the first step of the vitamin E metabolic pathway (8), as well as the metabolism of arachidonic acid (AA) to generate 20-hydroxyethyl hexadecanoic acid (20-HETE) through ω-hydroxylation (9). 20-HETE is known to promote tumorigenesis by increasing a variety of pro-inflammatory mediators, cytokines, and chemokines. Previous studies have demonstrated that the elevated expression of CYP4F2 enzymes and 20-HETE is closely related to ovarian cancer (10). We hypothesized that CYP4F2 might be involved in tumor genesis and development by accelerating the production of 20-HETE. Additionally, Geng et al. have proved that rs1558139 and rs2108622 of CYP4F2 are associated with hypertension, and the association between rs1558139 and hypertension is particularly strong in men (11). Despite this, there is a lack of studies investigating the association between CYP4F2 polymorphisms and LC risk.

In this case–control study, five SNPs (rs3093203, rs3093144, rs12459936, rs3093110, and rs3093193) in CYP4F2 were genotyped by the Agena MassARRAY platform. The gender- and smoking-stratified analyses on the correlation between CYP4F2 variants and LC risk were performed.

In our study, the connection between five variants in CYP4F2 and LC risk in the Chinese Han population was detected. Association analyses revealed that CYP4F2 rs12459936 increased susceptibility to LC in non-smoking individuals and females. In contrast, rs3093110 showed a protective effect on LC susceptibility in non-smoking groups and females. The two SNPs (rs3093193 and rs3093144) were also associated with a decreased risk of LC in females.

The CYP4F2 gene, a member of the CYP450 superfamily, located on chromosome 19p13.12, has been shown to be expressed at higher levels in certain types of cancerous tissues, such as the thyroid, ovarian, breast, and colon (10). Eun et al. have confirmed that low expression of CYP4F2 may contribute to the progression of hepatocellular carcinoma (HCC) and decrease survival rates due to its involvement in various metabolic pathways (15). A similar study showed that CYP4F2 expression was higher in pancreatic ductal adenocarcinoma (PDA) patients than in normal ones and negatively correlated with age (16). Database prediction found that CYP4F2 was highly expressed in lung cancer tissues. The expression of CYP4F2 was higher in men than women and higher in non-smokers than smokers. Additionally, Xu et al. have reported that CYP4F generates 20-HETE by catalyzing ω-hydroxylation of arachidonic acid (17). According to previous studies, 20-HETE plays a significant role in tumor progression. Colombero et al. have demonstrated that HET0016, a selective inhibitor of 20-HETE synthesis, can reduce the proliferation of prostate cancer (18), while another study has revealed that the antagonist of 20-HETE, WIT002, is able to inhibit tumor growth in a renal cell carcinoma cell line (19). This suggests that CYP4F2 polymorphisms may be related to susceptibility to LC by affecting the metabolism of 20-HETE, although further verification is required. Studies have also indicated a significant association between CYP4F2 polymorphisms and a variety of diseases, including ischemic stroke and various other cardiovascular and cerebrovascular diseases (12, 20).

Our study focused on the association between CYP4F2 polymorphisms and susceptibility to LC. Five sites were selected for statistical analyses: rs3093203, rs3093193, rs12459936, rs3093144, and rs3093110. However, none of these loci were found to be significantly associated with LC susceptibility under the allelic model or any of the five genetic models. The actual increase in LC risk may be underestimated due to the limited sample size. To further examine the potential influence of LC, we conducted a stratified analysis. Tobacco has long been recognized as an independent risk factor for tumorigenesis, as it contains many carcinogens, such as nitrosamines, polycyclic aromatic hydrocarbons, and volatile organic compounds (21). However, our analysis stratified by smoking revealed that the rs12459936 and rs3093110 loci were significantly associated with increased susceptibility to LC in the non-smoking population but not in the smoking population.

In addition, gender has been found to have a notable impact on the toxicity of therapeutic treatments and the response to them in many types of cancer. The underlying cause of this difference is likely related to a complex interplay of several factors, including sex hormones, which have been shown to affect the self-renewal of tumor stem cells, the tumor microenvironment, the immune system, and metabolism (22). It is well established that there are considerable differences in the immune system between men and women. In general, women have a stronger immune system than men, leading to distinct sex-based differences in both innate and adaptive immune responses. These disparities in immune systems likely play a role in cancer susceptibility between males and females (23). In our study, analysis stratified by gender was performed, and we found that rs309319, rs12459936, and rs3093110 all had a protective role against LC in females.

Taken together, our study observed that variants in CYP4F2 were associated with LC susceptibility. However, our research had some limitations. First, the potential functional implications of CYP4F2 polymorphisms were not addressed in this study. The expression data for CYP4F2 in LC cases were sourced from the database. To properly elucidate the genetic mechanism of CYP4F2 in LC, expression analysis of CYP4F2 mRNA and annotation of the functional significance of variants are necessary. Second, the sample size was relatively small. In the following steps, we will perfect this information and expand the sample size to explore the molecular mechanism of CYP4F2 polymorphisms affecting the development of LC.

The original contributions presented in the study are included in the article/ Supplementary Material , further inquiries can be directed to the corresponding author/s.

Our study complied with the Declaration of Helsinki, and the protocol in our experience was approved by the Second Affiliated Hospital of Xi’an Jiaotong University. All participants have been informed and provided written informed consent for the study.

HS designed this study and drafted the manuscript. YZ performed the DNA extraction and genotyping. YW revised the manuscript and performed the data analysis. PF and YL performed the samples collection and information recording. HS conceived and supervised the study. All authors contributed to the article and approved the submitted version.