In this study, we examined four SNPs of CYP19A1 gene in correlation to the susceptibility of lung cancer in a Chinese Han cohort. Statistical and bioinformatics results revealed the important roles of rs28757157 and rs59429575 in the outset of lung cancer in total or stratified population, which helped improve our understanding of CYP19A1 in this disease.
CYP19A1 gene encoding an aromatase responsible for the final step in the biosynthesis of estrogens, estradiol (E2) and estrone (E1), have been intensively investigated 22,23. SNPs in the intron region of CYP19A1 have been identified to play an important role in the transcriptional regulation and splicing of CYP19A1, producing some different enzymes with diverse enzyme activity compared with normal gene products. Variations in the allele frequency of several CYP19A1 SNPs have been documented in different populations and ethnic groups around the world. SNPs in CYP19A1 were found to be associated with cancer risk in European Americans, North Indians, and Chinese 24,25. In particular, CYP19A1 SNPs have been shown to be significantly associated with lung-related diseases.
A previous study has shown that SNP rs3764221 is significantly correlated with CYP19A1 expression in non-cancerous lung tissues, and affects the susceptibility of lung adenocarcinoma. The authors suggest that CYP19A1 polymorphisms may lead to elevated levels of local estrogen in the surrounding lung, and that this local excess estrogen production may be one of the factors associated with the polycentric development of adenocarcinoma 15. Recent result has suggested that CYP19A1 polymorphism is involved in lung bronchioloalveolar carcinoma and atypical adenomatous hyperplasia risk by causing differences in estrogen levels 16. It is clear that CYP19A1 polymorphism may cause changes in estrogen levels around the lungs, which in turn can affect the susceptibility of lung cancer.
Zhang et al. have shown that CYP19A1-rs727479 was significantly associated with the incidence of lung cancer. In particular, haplotype rs727479|rs730154|rs10046-ACA was only significantly associated with nonsmokers and female nonsmokers 17. These results indicated that CYP19A1 polymorphism is significantly associated with the susceptibility to lung cancer, and is gender-specific. Our research showed that CYP19A1-rs28757157 was associated with increased cancer risk in males and smoker, and CYP19A1-rs59429575 was identified as risk biomarker in female and lung adenocarcinoma patients. These two SNPs are located in the intron region of the CYP19A1 gene. Combined with previous studies and database predictions, we speculated that CYP19A1 intron single nucleotide polymorphisms may alter mRNA splicing, leading to changes in the activity of CYP19A1 and related estrogens, and may affect disease susceptibility. Since the statistical significance of the correlation between CYP19A1 gene polymorphism and the risk of lung cancer is slightly weak, further experimental studies are needed to verify the results of this study.
Our study has several limitations. All subjects were enrolled from the same hospital and the limitations of sample selection may affect the accuracy of this experiment. Additional studies that encompass more geographical regions, additional ethnic groups, and larger sample size should be performed. In order to verify the results of this study, it is necessary to clarify the relationship between CYP19A1 gene and lung cancer through subsequent functional studies.
In summary, our study defined two new SNPs of CYP19A1 that were significantly associated with lung cancer susceptibility. These variants may be considered as markers in lung cancer risk assessment for Chinese Han population.