WISP1 polymorphisms have been identified in various cancers, including breast cancer , urothelial cell carcinoma , hepatocellular carcinoma , oral squamous cell carcinoma , lung cancer , uterine cervical cancer , but data are scant as to the involvement of WISP1 polymorphisms in gastric cancer. As far as we are aware, our study is the first to investigate the distributions of the rs2929973, rs7843546 and rs10956697 SNPs and their associations with the development gastric cancer in Guangxi Chinese population. Our results revealed the correlations between WISP1 SNPs (rs7843546 and rs10956697) and gastric cancer susceptibility in different subgroups. In detailed, SNP rs7843546 TT and CT + TT genotype reduced the susceptibility to stage I/II gastric cancer with CC as a reference. The presence of the rs7843546 TT genotype was also associated with a significantly reduced risk of gastric cancer in Han population. In addition, we found that smokers or subjects ≥ 50 years old carrying the AC or AC + AA genotype of the WISP1 rs10956697 polymorphism were less likely than those with CC homozygotes to develop gastric cancer. Both of two SNPs were discovered for the first time to be associated with the gastric cancer.
Most previous researches about the association of WISP1 polymorphisms and cancer were focused on the polymorphisms of WISP1 SNPs rs2929970, rs2929973 and rs2977530. SNPs rs2929970 and rs2929973 are located in the 3'UTR of the WISP1 gene, and rs2977530 is located in introns. In the first second, in 2010, Frank et al. investigated the association between WISP1 SNP rs2929970 and colorectal cancer risk but found no evidence for the said risk . Then, in 2015, Chen et al. found that WISP1 SNP rs16893344, rs2977530, rs2977537, and rs62514004 polymorphisms were related to susceptibility of lung cancer, but found no significant association in SNPs rs2929970 or rs2929973 . By contrast, Lau et al. demonstrated that WISP1 SNP rs2929970 polymorphism carriers with at least one G allele were susceptible to oral squamous cell carcinoma in 2017 . Moreover, Chen et al. revealed that the WISP1 SNP rs2977530 (AG + GG) was associated with hepatocellular carcinoma development and WISP1 SNPs rs62514004 (AG + GG) and rs16893344 (CT + TT) were correlated with lower risks of greater tumor size and reaching a later clinical stage of hepatocellular carcinoma in 2018 . Furthermore, Lin et al. demonstrated genotypes AG + GG in WISP1 SNP rs2977530 reduced the susceptibility of Taiwanese women to invasive cervical cancer, whereas genotype AA in rs2977537 increases the said risk . In addition, Lee et al. indicated that patients with urothelial cell carcinoma carrying rs2977530 genetic variants (AG + GG) had a higher risk of developing a more invasive tumor stage and a large tumor . Wang et al. found that breast cancer patients with the WISP1 rs2929973 GG + TT genotype were likely to develop estrogen receptor (ER)- and progesterone receptor(PR)-positive tumors status .
Our study, however, revealed that the WISP1 rs7843546 and rs10956697 was associated with gastric cancer susceptibility in different subgroups, whereas no significant associations were observed in SNPs rs2929973. These results demonstrated the variety of WISP1 polymorphisms in different cancers. There are two reasons for these inconsistencies we may consider. One is that the WISP1 expression was varied in different cancer. Recent researches revealed that the roles of WISP1 in cancer occurrence and progression were diverse in different kinds of cancer. For example, WISP1 was found to negatively regulate the progress of cell motility and invasion by the inhibition of Rac function through integrins in lung cancer . On the contrary, WISP-1 was up-regulated in gastric cancer tissues compared with their adjacent noncancerous tissues, suggesting that WISP-1 acted as an oncogene in gastric cancer. Similar results were found in the previous studies in liver cancer  breast cancer , and endometrial adenocarcinoma . The other one reason is that different ethnicities of patients included in the aforementioned studies. Study of Frank  studied in Caucasians, but studies of Wang , Lin , Lee, Lau , Chen [16, 18, 21] studied in Asian. Our samples are south Chinese population that is East Asian. In particular, our results revealed that SNP rs7843546 TT genotype was associated with a significantly reduced risk of gastric cancer in Han population but no Zhuang population. This further indicated that WISP1 genotype distributions were different in different ethnicities.
Helicobacter pylori infection, aging, gender, smoking and alcohol consumption are the main risk factor for the development of gastric cancer . In order to rule out the influence of confounding factor: Helicobacter pylori infection, we did not include the Helicobacter pylori infection patients in our study. We further analyzed the correlations of WISP1 SNP polymorphisms with other confounding factors of gastric cancer patients. After stratifying individuals into smokers and nonsmokers, participants with AC genotype in WISP1 SNP rs10956697 displayed a 0.28-fold lower risk (95% CI = 0.09–0.82) of gastric cancer among the 132 smokers. Smoking is a well-known carcinogen for tumorigenesis, such as in gastric cancer, and nicotine exposure is suggested to promote cancer progression by activating the Wnt/β-catenin and Wnt/PCP signaling pathways . Aging is also a significant risk factor for gastric cancer. We stratified our included subjects according a person’s age. We found that subjects ≥ 50 years old carrying the WISP1 rs10956697 AC genotype were a 0.58-fold (95% CI = 0.35–0.98) lower risk than those with CC homozygotes to develop gastric cancer. Aging is the process of loss and degeneration of the body from constitutive substances and tissue structures to physiological functions . The time-dependent accumulation of cellular damage is widely considered the general cause of aging . Concomitantly, cellular damage may occasionally provide aberrant advantages to certain cells, which can eventually produce cancer .
The current findings must be interpreted in light of several potential limitations. Firstly, the evidence for different effects of aging, smoking, and ethnicity on gastric cancer risk was suggestive but not conclusive. Sample size for the study was not large enough and the sample size in each subgroup was even too small, thus, the results lack statistical power and robustness. Larger independent cohort study is required to confirm the result we discovered. Secondly, the study was limited to eligible participations in Guangxi (Southwest China), which might not be representative of the entire Chinese population. Thirdly, this research was based on data from individual participants and only 3 SNPs of the WISP1 gene were selected, which restricted interpretations about gene-to-gene interactions. These limitations restrict the interpretation and extrapolation of the current findings.