Introduction
Gastric cancer (GC) is the fifth most common cancer and the third main cause of cancer deaths, accounting for about 800,000 deaths annually [
1]. In popular, the common age of onset is 60 to eighty years, and under 30 years is rare. For this reason, GC is taken into consideration as an aging sickness [
2,
3]. The countries of East Asia, accompanied by Eastern Europe and South America, have the highest rates of infection. The lowest rates are observed in North America and Africa. However, the prevalence of GC has decreased in most countries, and regardless of advances in diagnosis, the ailment is normally recognized at advanced levels, in particular, because of the nonspecific nature of the signs within the early ranges. The average 5-year survival is only 20%. Further, surgical treatment and chemotherapy are of restricted value in treating advanced instances. Further, a wide variety of centered cures are available using molecular markers [
2].
GC is a multifactorial sickness that includes a way of life, aging, socioeconomic factors, infectious agents inclusive of Helicobacter pylori (classified as group 1 carcinogenic and associated with 80% of cases), Epstein-Barr virus (related to 10% of tumors), and multiple genetic and epigenetic versions [
3,
4]. Consistent with Loren’s type, gastric adenocarcinomas are divided into types: Intestinal (nicely differentiated with cohesive neoplastic cells, forming tubular gland-like systems) and diffuse (poorly differentiated with the aid of penetration and thickening of the gastric wall without discrete loads) [
5]. Those two kinds fluctuate now not handiest in histological evaluation, but additionally in sex, age, and other epidemiological functions [
2,
6,
7].
Colorectal cancer is the third most common tumor and the fourth leading cause of demise within the eastern world [
8]. The prevalence of this cancer varies from race to race; it is also related to age, diet, family history, smoking, sedentary lifestyle, and alcohol consumption [
9]. Another cause of colorectal cancer is polyps. Polyps are clusters of cells that develop within the middle of the colon. These polyps may transform into malignant tumors [
10]. Further to many of these factors, the function of genetic factors in the spread of colon cancer can’t be disregarded. One of the pathways in which the polymorphism of the involved genes is related to colorectal cancer is the insulin-signaling pathway [
11]. Insulin is a hormone secreted by beta cells inside the islets of the pancreas. This hormone’s function in regulating blood sugar (glucose) is known. Insulin controls cellular growth with the aid of binding to its receptor [
12] and prevents the deliberate loss of life of cells [
13]. From the factor of view of molecular biology, the insulin receptor is a membrane receptor that is activated by binding to insulin [
14]. After the insulin binds to its receptor, the subunits of the insulin receptor are phosphorylated and the insulin-signaling pathway for glycogen formation is decreased [
15]. Due to the fact tyrosine kinase receptors are involved in programmed cell death, metastasis, and cell growth and proliferation, their effect on malignancies isn’t unexpected [
16].
In place 5, there is an area of insulin receptor genes that is wealthy in GC, and transcription factors are attached to it [
17]. Polymorphism in this area causes a decrease in the degree of insulin receptor expression [
18,
19]. Numerous genetically related studies have shown that genetic changes on chromosome 9p21 can be concerned in numerous malignancies which include leukemia, glioma, ovarian, breast, and pancreatic cancers [
20‐
26]. This location is understood for the cyclin A and B-established kinase inhibitors called CDKN2A / B, which are involved in numerous metabolic and pathological issues consisting of diabetes, metabolic syndrome, cardiovascular disease, and Alzheimer’s [
27‐
30].
Current data have proven that the CDKN2A / B gene can alter cell increase by using stopping the cell cycle in section G1. Cell cycle progression inside the G1 phase is mainly modulated through the p14ARF, p15INK4B, and 16INK4A proteins ( [
27,
31,
32]). Tumor suppressor proteins p15INK4B and 16INK4A stop the cell cycle by decreasing cyclin-dependent kinases 4 and six (CDK4, 6), whilst p14ARF protein promotes apoptosis and mobile cycle by promoting the m5m2 -p signaling pathway through p5 mdmart [
33,
34]. Whilst the tumor suppressor’s p14ARF and p16INK4A are proven to be encoded by CDKN2A, the p15INK4B protein is encoded using CDKN2B [
34]. There’s new evidence that genes inside the CDKN2A / B locus genes were mutated or deleted in several human cancers. Several SNPs at the CDKN2A / 2B site lessen their expression and result in tumor cell proliferation and progression [
30,
35]. Current data have proven that deletion of CDKN2A / B is associated with poor prognosis and lower survival in patients with cutaneous T mobile lymphoma [
36]. In another large-scale meta-analysis study performed by Lou et al., the relationship between CDKN2A / B rs4977756 gene polymorphism and the risk of glioma in 18,893 patients without or with cancer was investigated. This evaluation showed that rs4977756 polymorphism is drastically related to the risk of glioma [
37]. Consistent with that research, the polymorphism correlation of the CDKN2A / B gene (rs10811661) was studied in 564 breast cancer sufferers and the outcomes confirmed that people with TT genotype have been extra susceptible to breast cancer [
38]. The affiliation of the two SNPs changed into assessment with the aid of CDKN2A / B locus (rs1333049 and rs10811661) and the clinical manifestations of esophageal squamous cell carcinoma (ESCC) and counseled that the CC rs1333049 genotype was polymorphically associated with a weaker overall prognosis [
39]. the aim of this study was to assess the association between the CDKN2A / B rs10811661 polymorphism, tumor grade and tumor invasiveness in individuals with colon and gastric cancer.
Discussion
In conclusion, our results advocate that there is a link between a CDKN2A / B gene polymorphism (rs10811661) and a poor prognosis in sufferers of colorectal and gastric cancer. Humans with the TT genotype were more susceptible to colorectal and gastric cancer. Consistent with our consequences, recent research has also proven the prognostic position of CDKN2A / B in pancreatic, lung, breast, melanoma, and ovarian cancers (Qiu et al., 2015 [
23]; Seifi et al., 2019 [
25]; Compa et al., 2016 [
40]; Schuster et al., 2014 [
41].).
Those observations can be defined by way of the function of CDKN2A / B in suppressing cell proliferation and inducing tumor cellular dying. Numerous studies have proven that methylation or dysregulation of ANRIL may lessen CDKN2A / B and its downstream tumor suppressants (p14ARF and p16INK4A), which main to tumor formation and progression [
42]. ANRIL has been proven to play a prime function in promoting transcriptional suppressors concerned within the discount of CDKN2A / B genes, leading to the genetic predisposition to diverse cancers (Congrains et al., 2013 [
20]; Yap et al., 2010 [
43]; Popov & Gil, 2010 [
44]).
In keeping with this data, sun et al. ANRIL expression changed into tested in 97 tumor and non-tumor tissue samples of the CRC placenta. They found that overexpression of ANRIL in tumor tissues was related to lower survival in CRC sufferers. in addition, their laboratory results confirmed that reduction of ANRIL in CRC cell strains decreased cell proliferation and invasion (sun et al., 2016 [
45]).
In another study, the correlation between ANRIL expression and clinical pathological functions of CRC became investigated in 108 sufferers. Their results indicated that overexpression of ANRIL in a CRC patient may be taken into consideration as a risk aspect for poor diagnosis and tumor metastasis (sun et al., 2016 [
46]). However, the potential function of ANRIL in colorectal tumorigenesis has now not yet been decided. Recently, a huge-scale genomic correlation takes a look at was accomplished to research the association of 9p21 locus SNPs and the risk of neoplastic transformation in a couple of cancers. Their data showed that there are different genetic variations in this region related to the development of various types of cancer (Lee et al., 2014 [
47]). In line with this, Gu et al. 203 analyzed SNP in the 9p21.3 area in several cancers, which include colorectal cancer. Their findings endorse that genetic variants in CDKN2A can be associated with an increased risk of colorectal cancers and other tumors (Gu et al., 2013 [
24]).
Past research has shown that polymorphisms in insulin-resistant genes are effective on insulin resistance and weight gain [
48,
49] as well as on the risk of developing colon cancer [
50,
51]. Insulin receptors, or a decrease in insulin binding to the receptor, cause the genetic syndrome of insulin resistance [
52], which in itself is a robust thing in growing the risk of developing colorectal cancer.
Ghobadi and colleagues 2019, after examining the relationship between rs10811661 and rs1333049 polymorphisms in chromosome 9 P21 locus in CDKN2A / B gene, patients with esophageal squamous cell carcinoma (ESCC) and healthy individuals concluded that in patients with carcinoma cancer, Esophageal squamous cells had a higher frequency of TT genotype for rs10811661 polymorphism than the control group and tumor size was reported to be larger in affected individuals. In addition, the mortality rate was higher in patients with CC genotype for rs1333049 polymorphism [
53].
Hesari et al. 2018, in research on the 2 polymorphisms of rs1801133 in methylene tetrahydrofolate reductase and rs10811661 in CDKN2A / B in patients with breast cancers, concluded that the frequency of T allele and TT genotype in methylene tetrahydrofolate reductase gene was more prevalent in patients than in the control group. The frequency of the C allele in rs10811661’s CDKN2A / B gene was 72%. The results of the present observation are consistent with the effects of studies [
54].
In a study conducted in 2018 by ShahidSales et al. On the association of rs10811661 polymorphism in CDKN2A / B in healthy and breast cancer patients, they concluded that the frequency of TT genotype was higher in breast cancer patients than in the control group. In these people, the size of the tumor is also reported to be larger. In addition, genetic studies in these individuals have shown that people with TT genotype are more likely to develop breast cancer than those with CC / CT genotypes [
55].
In 2020, Rahmani et al. studied the association between rs10811661 polymorphism and colorectal cancer in 541 healthy and diseased individuals. Their research method was Taq-Man-based real-time PCR. The results confirmed the effect of this polymorphism on colorectal cancer and introduced this polymorphism as a suitable biomarker for predicting this cancer [56].
Consistent with these observations, our data support a sizeable association between CDKN2A / B gene polymorphisms, rs10811661, and colorectal and gastric cancers.
In this study, a similar result was observed, which indicates a direct relationship between TT genotype in rs10811661 polymorphism with gastric and colon cancer, tumor invasiveness, and tumor grade. In addition, there was a difference in the degree of dependence of gastric and colon cancer on the rs10811661 polymorphism genotype with sex, but the grade and aggressiveness of the tumor were not particularly dependent on the sex of the patient. Also, in different genotypes, the percentage of the frequency distribution of different phases of invasiveness and tumor grade was different, which indicates the effect of this polymorphism on these two characteristics, and also the highest frequency of tumor grade in CC grade I, in grade II CT and grade III TT and the highest percentage of T3 phase frequency, tumor invasiveness was also observed in TT condition.
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