Genetic polymorphisms of CYP24A1 gene and cancer susceptibility: a meta-analysis including 40640 subjects

Cancer is a global public health problem, and incidence and mortality are rapidly growing worldwide. According to the data of the International Agency for Research on Cancer, GLOBOCAN 2020 investigation results showed 19.3 million new cancer cases and 10.0 million cancer deaths in 2020 [1]. In 2023, it is estimated that there will be 1,958,310 new cancer cases and 609,820 cancer-related deaths in the USA [2]. With the rapid growth and aging of the world population, the predominance of cancer is a leading cause of death. Current evidence suggests that factors, such as irregular lifestyles, smoking, alcohol intake, environmental factors, and genetic factors, are closely associated with the occurrence of cancer [1, 2]. Accumulative evidence has demonstrated that genetic factors may be associated with the etiology of cancer and the individual’s risk of cancer development, especially whole-genome association studies (GWAS) have identified various genes that may be involved in cancer development [3, 4].

Vitamin D, an essential fat-soluble vitamin, is mainly come from ultraviolet exposure and diet metabolism [5]. Meanwhile, it plays critical roles in cellular growth and anti-proliferative activities [6]. Clinical studies have indicated that vitamin D deficiency contributed to cancer risk, including prostate cancer, breast cancer, and thyroid carcinoma [7]. 25 hydroxy vitamin D (25(OH)D) is the main circulating form of vitamin D. In addition, 1,25 dihydroxy vitamin D (1,25(OH)2D3), an active form of vitamin D, which is associated with cell functions and gene expression. In the process of vitamin D metabolism, 25(OH)D and 1,25(OH)2D3 are converted to 24,25 dihydroxy vitamin D (24,25(OH)2D3) and 1,24,25 trihydroxy vitamin D (1,24,25(OH)3D3), respectively, which are degraded by 25-hydroxyvitamin D 24-hydrolase (encoded by CYP24A1 gene) [8]. Mutation of CYP24A1 may influence the metabolism of Vitamin D and anti-proliferative effects [9, 10].

Single-nucleotide polymorphisms (SNPs) are the most common form of variation in the human genome, which can alter the expression level or function of genes or their encoded products and thus determine the phenotype of the organism [11, 12]. Therefore, it is increasingly recognized that SNPs play a crucial role in the mechanisms of cancer [13]. Epidemiological studies have demonstrated that several common SNPs of CYP24A1 are involved in the concentration of circulating 25(OH)D [14]. To date, five common SNPs (rs4809960, rs6068816, rs2296241, rs4809957, rs2762939) were found to be associated with cancer risk, including esophageal squamous cell carcinoma prostate cancer, breast cancer, and lung cancer [5, 14, 15]. However, controversial results were reported and the association was not yet well established. Therefore, a comprehensive meta-analysis was performed to better explore the associations of CYP24A1 polymorphisms with cancer risk.

This study was performed under the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and was registered in PROSPERO (CRD42023446451).

CYP24A1, a member of the cytochrome P450 enzyme family, is located on the long arm of chromosome 20 (20q13.2). It is a key gene that converted 1,25(OH)2D3 to 1,24,25(OH)2D3 by 24-hydroxylation25-hydroxyvitamin D 24-hydrolase [34]. Albertson et al. [35] first identified the 20q13 gene amplification in breast cancer and identified the CYP24A1 gene as a candidate oncogene using array comparative genomic hybridization. CYP24A1 has been identified as a potential biomarker for cancer [36]. Numerous studies have suggested the expression level of the CYP24A1 was abnormally increased in several cancers, such as breast cancer, ovarian cancer, cervix carcinoma, lung cancer, and colon cancer [7, 37, 38]. Kong et al. [39] revealed that the rs6068816 and rs4809957 polymorphisms were associated with NSCLC risk. For breast cancer, Wei et al. [27] reported a significant association between the rs4809957 and breast cancer risk. Anderson et al. [18] revealed no significant correlation between rs4809957 with pancreas cancer. Among these publications reported the associations of CYP24A1 polymorphisms with cancer susceptibility, while the results remain controversial. The previous meta-analysis was performed by Zhu et al. [40], but they had not controlled the type I error rate through Bonferroni correction and had a smaller sample size. Therefore, the present meta-analysis aimed to re-evaluate the associations of CYP24A1 polymorphisms with cancer risk.

The present study indicated that there was no association between CYP24A1 polymorphisms (rs4809960, rs2296241, rs4809957, rs2762939, rs6068816) and overall cancer risk. For rs4809960 polymorphism, it was related to the Caucasian and Asian populations and decreased breast cancer risk. Moreover, our results suggested that rs2296241 polymorphism increased esophageal squamous cell carcinoma risk and decreased prostate cancer risk. For rs4809957 polymorphism, it was associated with pancreas cancer and breast cancer risk. In addition, we found that rs6068816 polymorphism significantly decreased lung cancer and breast cancer risk. However, rs4809960 polymorphism was associated with a decreased breast cancer risk after Bonferroni correction. A previous meta-analysis also reported CYP24A1 rs2296241 polymorphism was associated with prostate cancer risk [41]. Although our work found rs2296241 polymorphism was associated with an increased esophageal squamous cell carcinoma risk and decreased prostate cancer risk, these results could not withstand the Bonferroni correction.

The improvements of our meta-analysis are as follows: Firstly, more case-control studies about rs4809960, rs6068816, and rs2296241 polymorphism were included in the meta-analysis. Secondly, this is the first meta-analysis to assess the relationship between CYP24A1 (rs4809957, rs2762939) polymorphism and cancer risk. Thirdly, all included studies conform to the HWE, which may improve the reliability and stability of our study. In addition, all CYP24A1 polymorphisms were considered at the beginning. Ultimately, due to a lack of eligible articles and overlapping studies, our further evaluation of other CYP24A1 polymorphisms was limited. Therefore, in this meta-analysis, we only focused on five polymorphisms.

There are several limitations should be noted in the present study. First, the sample size of the included studies was relatively small, which might weaken the strength of the results. Second, the number of included studies in the subgroup analysis was also relatively small, which might lead to statistical bias. Third, not sufficient data to analyze whether environmental factors may influence the statistical result. Four, the association of CYP24A1 polymorphism with different types or stages, drinking, smoking, age, gender, exposure factors, or other risk factors was not considered in this study. Five, the patients of included studies mainly come from Caucasians. The African and Asian populations were relatively small.

In conclusion, this meta-analysis indicated that rs4809960 polymorphism was associated with a decreased breast cancer risk. No association between rs4809957, rs2296241, rs2762939, rs4809957 polymorphism, and overall cancer risk was found after Bonferroni correction. Considering the above limitations, more large-scale and large-sample studies are necessary to confirm these results.