Discussion
Somatic mutations in oncogenes and tumor suppressor genes, in collaboration with environmental exposures such as tobacco and carcinogenic chemicals, can trigger cancer.
While hereditary cancers account for only 5–10% of all cases and are associated with germline alterations in oncogenes and tumor suppressor genes, non-hereditary cancer can be predisposed by single-nucleotide polymorphisms (SNPs). These genetic variants, known as “drivers,” primarily cause uncontrolled cellular proliferation and occur in “cancer driver genes” [30]. A recent study identified about 570 cancer driver genes that mediate molecular regulatory networks and changes in the tumor microenvironment. Mutations in these genes, as well as abnormal expression levels, can lead to uncontrolled tumor cell proliferation, invasion, and drug resistance [31].
Some case–control studies have shown a correlation between SNPs and susceptibility to gastric cancer in the Ardabil population. Among these, the relationship between IL-1β-511 and MTHFR C677T polymorphisms and gastric cancer is notable [
32,
33]. However, some SNPs previously reported as gastric cancer-related variants were not associated with this population, including the polymorphism P53 Arg72Pro [
34].
Previous studies have suggested an important role of miR-149 in carcinogenesis. This microRNA acts as a tumor suppressor gene in some cancers and an oncogene in others. Upregulation of miR-149 has been reported in AML, prostate cancer, glioblastoma, and melanoma, while it is downregulated in gastric, hepatocellular, renal cell, lung, colorectal, breast, and thyroid cancers, as well as neuroblastoma. Upregulation of miR-149 in tumor cells and gastric cancer cell lines inhibits cell proliferation and induces G0/G1 cell cycle arrest [
35].
In our general population, the frequency of the C allele of rs2292832 (a T to C nucleotide change in miR-149) was found to be the lowest (0.51 vs. 0.64 for Iran, 0.7 for Europe, and 0.7 for the world), indicating a significant difference (
P = 0.017). Consistent with this finding, a lower frequency of the C allele (
P = 0.001) and the genotypes TC (
P = 0.046), CC (
P = 0.01), and TC+CC (
P = 0.01) were observed compared to the controls. Based on the reported relationship between a reduced risk of gastric cancer and the rs2292832 C allele in two case–control studies on Chinese and Korean populations, as well as a meta-analysis [
36,
37,
38], the lower frequency of the C allele in Ardabil could be associated with a higher risk of gastric cancer. However, the absence of deviation from Hardy–Weinberg equilibrium and the lack of association in other studies [
39,
40,
41] necessitate further research, including cohort investigations, in our population.
The variant rs12983273 C>T is located in the MIR371B and MIR373 genes. It has been reported that hsa-miR-373 is downregulated in the gastric cancer recurrent group [
42]. PRDM4, which has been identified as a risk biomarker for gastric cancer patients, is regulated by hsa-miR-373 [
43]. In addition to the upregulation of miR373 in gastric adenocarcinoma tissue and gastric carcinoma cell lines, the inhibition of migration and invasion in some gastric cancer cell lines has been observed [
44].
There were no reported associations for rs12983273 and female neoplasm, breast cancer, ESCC, Oral Premalignant Lesions (OPL), and esophageal cancer risk [
45]. Compared to Iranian, European, and world populations, the T allele has a lower frequency in Ardabil (0.107 vs. 0.136). This difference tends to be significant (
P = 0.017). Consistent with this finding, the frequency of allele T and genotype CT+TT in cases affected with gastric cancer were lower than in controls (
P values of 0.02 and 0.031, respectively). Cohort studies are needed to validate the impact of rs12983273 in conferring gastric cancer predisposition in our population.