WITHDRAWN: Polymorphisms rs2073618 and rs3102735 in TNFRSF11B with the Susceptibility to Gastric Cancer

doi:10.21203/rs.3.rs-4872627/v1

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WITHDRAWN: Polymorphisms rs2073618 and rs3102735 in TNFRSF11B with the Susceptibility to Gastric Cancer

https://doi.org/10.21203/rs.3.rs-4872627/v1

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Purpose

This study aims to explore the potential association between TNFRSF11B gene polymorphisms (rs2073618 and rs3102735) and the risk of gastric cancer in the Chinese Han population.

Methods

A case-control study was conducted involving 577 individuals diagnosed with primary gastric cancer and 678 healthy volunteers. Genomic DNA was extracted from whole blood samples, and the target gene fragment was amplified via PCR. Genotyping and allele analysis were subsequently performed using the snapshot technique.

Results

In this retrospective research, it was discovered that the TNFRSF11B rs3102735 T > C polymorphism is significantly correlated with a heightened risk of gastric cancer. Conversely, the variant allele of the rs2073618 polymorphism demonstrated no significant association with susceptibility to gastric cancer. During the subgroup analysis of the rs3102735 polymorphism, a notably heightened risk of gastric cancer was observed in the group aged above 62 years. Stratified analyses indicated that the TNFRSF11B rs2073618 polymorphism didn’t exhibit an association with gastric cancer susceptibility across varying ages, genders, smoking and alcohol drinking.

Conclusion

Our research indicated a link between smoking and the incidence of gastric cancer. Additionally, we identified a link between gastric cancer and the TNFRSF11B rs3102735 polymorphism, but not with the rs2073618 polymorphism. TNFRSF11B rs3102735 CC mutated homozygote genotype may be an indicator of gastric cancer.

Biological sciences/Cancer

Biological sciences/Genetics

gastric cancer

TNFRSF11B gene

single nucleotide polymorphism (SNP)

rs2073618

rs3102735

As per the most recent figures, the year 2018 witnessed approximately 1.03 million fresh diagnoses of gastric cancer, along with 780,000 deaths from the disease across the globe. This places gastric cancer as the fifth most prevalent malignancy in terms of incidence and the third deadliest in terms of mortality ^[1]. China grapples with a notably high rate of gastric cancer, contributing to roughly half of the global count of new cases and fatalities associated with the disease ^[2]. Gastric cancer represents a significant peril to both the physiological and psychological welfare of individuals. However, due to the atypical early symptoms of gastric cancer and the delay in detection, gastric cancer is often found in the advanced stage, which seriously affects the prognosis. The precise pathogenesis of gastric cancer remains elusive. The incidence of gastric cancer is tied to a plethora of factors, spanning both environmental and genetic influences ^[3]. Therefore, studying gastric cancer's pathogenesis at the molecular level will contribute to the prevention, diagnosis, and subsequent treatment of gastric cancer.

Some studies demonstrate that human susceptibility to cancer may be closely related to single nucleotide polymorphisms (SNPs) ^{[4, 5]}. SNP represents the predominant form of inheritable variation within the human species, which can lead to DNA sequence polymorphism, including insertion or deletion of bases, as well as inversion and conversion of bases, which can lead to changes in corresponding amino acids, leading to differences in susceptibility to tumors ^[6].

The TNFRSF11B gene, commonly known as osteoprotegerin (OPG), is a member of the prestigious tumor necrosis factor receptor superfamily. TNFRSF11B assumes a critical role in impeding the formation, differentiation, and lifespan of osteoclasts (OC), concurrently promoting apoptosis in these cells. This function is complexly intertwined with the receptor activator of nuclear factor-kappa B (RANK) and its ligand, the receptor activator of nuclear factor-kappa B ligand (RANKL) ^[7]. Moreover, TNFRSF11B is also linked with another constituent of the tumor necrosis factor family ligand, specifically TRAIL (TNF-related apoptosis-inducing ligand), a TNF-analog cell surface molecule that is pivotal in initiating apoptosis within cancer cells ^[8]. TNFRSF11B is thought to be one of the few decoy receptors in TRAIL to modulate its ability to target cancer cells. Studies have found that TNFRSF11B assumes a crucial role in the genesis and progression of certain malignant tumors ^[9–11]. In recent years, it has been discovered that TNFRSF11B exhibits high expression levels in gastric cancer cell lines, primary tumors, and bone metastases ^[12]. Recently, the biological functions and molecular mechanisms of TNFRSF11B in gastric cancer have undergone extensive investigation. Researchers have identified a novel regulation of the GSK3β/β-catenin pathway by TNFRSF11B, suggesting that it may serve as a biomarker and a clinical target for the treatment of gastric cancer ^[13]. At present, there have been many studies on SNPs of gastric cancer susceptibility genes ^[14–20]. However, there has been no documented report that elucidates the connection between polymorphisms in the TNFRSF11B gene and the incidence of gastric cancer ^[14–26].

Based on previous research, we hypothesized that polymorphisms in the TNFRSF11B gene might be associated with an increased susceptibility to gastric cancer. Hence, our study entailed a detailed comparison of the genotypes and alleles for the rs2073618 and rs3102735 markers within the TNFRSF11B gene among gastric cancer patients and control groups, utilizing a case-control strategy. Subsequently, we delved into an analysis to uncover any potential associations between TNFRSF11B gene polymorphisms and the vulnerability to developing gastric cancer. Simultaneously, we integrated clinical parameters of the patients, including gender, age, smoking history, and drinking history, into our analysis. We conducted an exhaustive analysis of the interrelation among these factors to furnish a robust theoretical foundation for the early detection and therapeutic intervention of gastric cancer.

2.1 Research Object

In our study, we enlisted a cohort comprising 577 individuals diagnosed with gastric cancer, alongside 678 healthy control participants. The case group consisted of patients receiving treatment for gastric cancer at Zhenjiang First People's Hospital during the period extending from May 2013 to June 2017.The people in the control group were healthy people who received medical examinations at the Zhenjiang First People's Hospital during the same period. The average age of individuals in the case group was 61.34 ± 11.097 years, encompassing 394 men and 183 women. All patients were Chinese, ethnic Han. Each case was verified through clinical and pathological diagnosis as primary gastric cancer, explicitly excluding instances of secondary or recurrent tumors as well as other forms of malignant tumors. Prior to the commencement of the experiment, none of the patients had been subjected to radiotherapy or chemotherapy. The control group presented an average age of 62.31 ± 7.549 years, comprising 456 males and 222 females, and was distinguished by an absence of any prior genetic history related to the tumor. The case and control groups were carefully matched for gender and age, ensuring additionally that there was no blood relation between the members of either group.

2.2 The Research Method

We adhered to the methodologies outlined by Fan ^[11] et al. The collection of disease history information for both the case group and the control group was conducted by personnel who had undergone uniform training. This process was further reinforced by the implementation of a double-entry system and thorough logic verification to guarantee the precision of the data gathered. A volume of 2mL of venous blood was meticulously drawn by professional nurses adhering stringently to principles of sterilization, with EDTA employed as the anticoagulant agent. Following centrifugation, the residual whole blood was utilized for the extraction of genomic DNA. The extraction process was conducted according to the instructions. After DNA extraction, a protein-nucleic acid detector was used to detect the purity and concentration for subsequent experiments. Samples failing to fulfill the specified ratio criteria were promptly discarded. The design of upstream and downstream primers, as well as the Snapshot typing extension primers for the gene TNFRSF11B rs2073618 and rs3102735, was adeptly conducted using Premier 5 software. The primers were expertly synthesized by Furui Bioengineering Co., Ltd., resulting in a product length of 201 bp through PCR amplification. Subsequent to amplification, the PCR products underwent purification utilizing ExoI and FastAP, followed by an extension process. After the extension process, the ABI3730XL sequencer was used for detailed sequencing and genotyping. Gene polymorphism detection was conducted using Snapshot technology. To guarantee the precision of the detection outcomes, 5% of the samples were randomly chosen for reevaluation.

2.3 Statistical Methods

Statistical analyses were conducted using SPSS 20.0 (SPSS Inc., Chicago, IL, USA). The frequency of genotype distribution in both the control and case groups was checked for compliance with Hardy-Weinberg equilibrium. The chi-square (χ2) test was used to evaluate the genotype distributions of TNFRSF11B rs2073618 G > C and rs3102735 T > C, with the goal of identifying statistical differences between patients and control subjects. The odds ratio (OR) and the corresponding 95% confidence interval (CI) were determined through binary logistic regression analysis to evaluate the relative risk associated with specific genotypes or alleles present at a polymorphic locus. Haploview software played a crucial role in executing haploview analysis. Statistical examinations were conducted as bilateral probability tests, with a P-value less than 0.05 earmarked as the threshold for statistical significance.

3.1 Primary information for gene TNFRSF11B rs2073618 and rs3102735 polymorphisms

Table 1 the frequency distribution of genotypes for rs2073618 and rs3102735 polymorphisms within the control group adhered to Hardy-Weinberg equilibrium (P-value for HWE, all P > 0.05).

Table 1

Primary information for gene *TNFRSF11B* rs2073618, rs3102735 polymorphisms
Genotyped SNPs	Gene	Chr Pos (NCBI Build 38)	Category	MAF^a for Chinese in database	MAF in our controls (n = 678)	P value for HWE^b test in our controls	Genotyping value (%)
rs2073618	TNFRSF11B	chr8:118951813	Mission variant	0.394	0.095	0.435	95.72
rs3102735	TNFRSF11B	chr8:118952831	Intron Variant	0.145	0.021	0.180	94.98
genotyping method: snapshot

3.2 Characteristics of the study population

The characteristics of 577 GC and 678 control subjects are summarized in Table 2, encompassing both demographic details and environmental risk factors. The matching of controls and cases was rigorously conducted with respect to age and gender, demonstrating no significant disparity (χ2 test, P = 0.065 and 0.063, respectively). Significantly, the prevalence of smoking was significantly greater in the case group compared to the control group (34.49% vs 27.29%, P < 0.006), which suggests a substantial link between smoking behaviors and the likelihood of developing gastric cancer. Conversely, the comparison revealed no noteworthy difference in alcohol use rates between the case and control groups, indicating its negligible impact on GC risk.

Table 2

Distribution of selected demographic variables and risk factors in gastric cancer cases and controls
	Overall Cases (n = 577)	Overall Controls (n = 678)	P
	n (%)	n (%)
Age (years)	61.34 ± 11.097	62.31 ± 7.549	0.065
Age (years)
< 62	268 (46.45)	324 (47.79)
≥ 62	309(53.55)	354(52.21)	0.635
Sex
Male	394 (68.28)	456(67.26)
Female	183(31.72)	222(32.74)	0.698
Smoking status
Never	378 (65.51)	493(72.71)
Ever	199(34.49)	185 (27.29)	0.006
Alcohol use
Never	453 (78.51)	520(76.70)
Ever	124 (21.49)	158(23.30)	0.443

3.3 Association of TNFRSF11B rs2073618 polymorphisms with gastric cancer.

The genotype data for the TNFRSF11B rs2073618 G > C polymorphism is meticulously detailed in Table 3. Nonetheless, the analysis revealed that the frequency of genotypes for the TNFRSF11B rs2073618 SNP does not significantly diverge between the cases and controls (P > 0.05).

Table 3

rs2073618 polymorphism in GC cases and controls and logistic regression analysis
Genotype	GC Cases (n = 577)		Controls (n = 678)		OR (95%CI)	P
Genotype	n	%	n	%
rs2073618
GG	304	53.15	353	54.40	1.00
CG	227	39.69	246	37.90	1.071(0.846–1.358)	0.568
CC	41	7.16	50	7.70	0.952(0.613–1.479)	0.827
CG + CC	268	46.85	296	45.60	1.051(0.839–1.317)	0.663
CC	41	7.16	50	7.70	0.925(0.602–1.421)	0.722
CG + GG	531	92.84	599	92.30	1.00

3.4 Association of TNFRSF11B rs3102735 polymorphisms with gastric cancer.

For TNFRSF11B rs3102735 T > C polymorphism, the increased risk of gastric cancer was found in two genetic models. The results in the Table 4 showed that when the TT homozygote genotype was used as the reference type, the frequency distribution of CC mutated homozygote genotype was higher in the case group than that in the control group (CC vs.TT: OR = 2.164, 95% CI = 1.063–4.406, p = 0.030). In the recessive model, the frequency distribution showed a statistically significant difference. (.CC vs.TT + CT: OR = 2.290, 95% CI = 1.129–4.646, p = 0.018).

Table 4

rs3102735 variation in gastric cancer cohorts and control groups with logistic regression examination
Genotype	GC Cases (n = 577)		Controls (n = 678)		OR (95%CI)	P
Genotype	n	%	n	%
rs3102735
TT	395	71.56	446	69.25	1.00
CT	134	24.28	186	28.89	0.813(0.627–1.055)	0.119
CC	23	41.67	12	1.86	2.164(1.063–4.406)	0.030
CT + CC	157	65.95	198	30.75	0.859(0.698–1.149)	0.385
CC	23	41.67	12	1.86	2.290(1.129–4.646)	0.018
CT + TT	529	95.84	632	98.14	1.00

3.5 Analysis of TNFRSF11B rs2073618 and rs3102735 alleles between cases and controls

The findings presented in Table 5 illustrate that the distribution of allele frequencies for rs2073618 and rs3102735 within the TNFRSF11B gene exhibit no significant variation between the case group and the control group (P = 0.844, P = 1.000).

Table 5

Examination of rs2073618 and rs3102735 alleles in cases versus controls
Locus	Variable	Case	Control	OR (95% CI)	P
rs2073618	G allele	835(72.99)	952(73.34)	1.018(0.851–1.218)	0.844
rs2073618	C allele	309(27.01)	346(26.66)
rs3102735	T allele	924(83.70)	1078(83.70)
rs3102735	C allele	180(16.30)	210(16.30)	1.000(0.804–1.243)	1.000

3.6 Association of TNFRSF11B rs2073618 and rs3102735 polymorphisms with GC in Different Stratification Groups

To delve deeper into the potential impact of the TNFRSF11B rs2073618 and rs3102735 polymorphisms on gastric cancer (GC) susceptibility, a series of stratification analyses were conducted. These analyses considered several factors such as age, gender, smoking habits, and alcohol consumption status, with the results comprehensively displayed in Tables 6 and 7.

The findings presented in Table 6 reveal that, following stratified analysis of the TNFRSF11B rs2073618 G > C polymorphism did not exhibit a correlation with gastric cancer (GC) risk within the subgroups.

Table 6

Segregated assessments of the rs2073618 polymorphism and associated risk stratified by gender, age, smoking habits, and alcohol intake
Variable	(case/control)			Adjusted OR (95% CI); P
Variable	GG	CG	CC	GG	CG	CC	VSGG (CG + CC)	CCVS(GG + CG)
Sex
Male	212/228	154/173	26/38	1.00	0.957(0.719–1.275); P(0.766)	0.736(0.432–1.254); P(0.258)	0.917(0.698–1.205); P(0.536)	0.750(0.446–1.259); P (0.275)
Female	92/125	73/73	15/12	1.00	1.359(0.891–2.071); P (0.154)	1.698(0.759-3.800); P (0.194)	1.407(0.941–2.102); P (0.095)	1.500(0.683–3.294); P (0.310)
Age
< 62	128/162	117/127	20/19	1.00	1.166(0.828–1.641); P (0.378)	1.332(0.682–2.602); P (0.400)	1.188(0.855–1.650); P (0.305)	0.799(0.448–1.426); P (0.447)
≥ 62	176/191	110/119	21/31	1.00	1.003(0.721–1.386); P (0.985)	0.735(0.407–1.327); P (0.306)	0.948(0.694–1.294); P (0.735)	0.746(0.419–1.328); P (0.318)
Smoking status
Never	194/261	154/177	25/30	1.00	1.171(0.880–1.556); P (0.279)	1.121(0.639–1.967); P (0.690)	1.163(0.885–1.529); P (0.277)	1.049(0.606–1.816); P (0.865)
Ever	110/92	73/69	16/20	1.00	0.885(0.516–1.360); P (0.577)	0.669(0.328–1.365); P (0.268)	0.836(0.559–1.252); P (0.386)	0.951(0.671–1.347); P (0.776)
Alcohol consumption
Never	238/273	175/188	35/33	1.00	1.068(0.816–1.398); P (0.633)	1.217(0.733–2.019); P (0.447)	1.090(0.843–1.409); P (0.511)	1.184(0.723–1.940); P (0.502)
Ever	66/80	52/58	6/17	1.00	1.087(0.662–1.785); P (0.743)	0.428(0.160–1.147); P (0.085)	0.937(0.584–1.504); P (0.789)	0.413(0.158–1.081); P (0.064)

Table 7 outlines the relationship between the TNFRSF11B rs3102735 T > C polymorphism and the risk of gastric cancer as discerned from stratified analyses. It was observed that individuals carrying the CC mutated homozygote genotype in the subgroup which ages ≥ 62 were at a heightened risk for developing gastric cancer (CC vs. TT: adjusted OR = 5.44, 95% CI 1.54–19.21, P = 0.003). Under the recessive genetic model, a statistically significant disparity in the frequency of the CC homozygous mutation was observed between the comparison groups (CC vs. TT + CT: adjusted OR = 5.54, 95% Confidence Interval 1.58–19.47, P = 0.003).

Table 7

Stratified analyses between rs3102735 polymorphism and risk by sex, age, smoking status and alcohol consumption
Variable	(case/control)			Adjusted OR (95% CI); P
Variable	TT	CT	CC	TT	CT	CC	VSTT (CT + CC)	CCVS (TT + CT)
Sex
Male	265/2 96	97/12 5	15/10	1.00	0.87(0.63- 1.19); P:0.370	1.68(0.74- 3.79); P:0.211	0.93(0.69- 1.25); P:0.619	1.74(0.77- 3.92); P:0.176
Female	130/1 50	37/61	8/2	1.00	0.70(0.44- 1.12); P:0.137	4.62(0.96- 22.12); P:0.052	0.84(0.54- 1.32); P:0.452	5.05(1.06- 24.11); P:0.025
Age
< 62	191/2 08	55/88	9/9	1.00	0.68(0.46- 1.01); P:0.055	1.09(0.42- 2.80); P:0.860	0.72(0.50- 1.04); P:0.081	1.20(0.47- 3.08); P:0.699
≥ 62	204/2 38	79/98	14/3	1.00	0.94(0.66- 1.34); P:0.731	5.44(1.54- 19.21); P:0.003	1.07(0.77- 1.51); P:0.678	5.54(1.58- 19.47); P:0.003
Smoking status
Never	258/3 24	87/13 4	15/9	1.00	0.82(0.60- 1.12); P:0.204	2.09(0.90- 4.86); P:0.080	0.90(0.66- 1.21); P:0.475	2.21(0.96- 5.11); P:0.057
Ever	137/1 22	47/52	8/3	1.00	0.81(0.51- 1.28); P:0.359	2.38(0.62- 9.15); P:0.231	0.89(0.57- 1.39); P:0.611	2.52(0.66- 9.66); P:0.163
Alcohol consumption
Never	310/3 42	108/14 2	17/10	1.00	0.84(0.63- 1.13); P:0.241	1.88(0.85- 4.16); P:0.116	0.91(0.68- 1.20); P:0.499	1.97(0.89- 4.35); P:0.088
Ever	85/1 04	26/44	6/2	1.00	0.72(0.41- 1.27); P:0.258	3.67(0.72- 18.66); P:0.095	0.85(0.50- 1.45); P:0.554	4.00(0.79- 20.19); P:0.071

3.7 Haplotype analysis

Analyses of haplotypes for TNFRSF11 gene polymorphisms rs2073618 and rs3102735 in relation to the risk of GC, as demonstrated in Table 8, showed no significant differences between cases and controls.

Table 8

Haplotype analysis
	Case(freq)	Control(freq)	Chi²	Pearson's P	Odds Ratio [95%CI]
C C*	15.80(1.4)	20.96(1.7)	-	-
C T*	279.20(25.5)	309.04(25.0)	0.041	0.839	1.020 [0.845 ~ 1.230]
G C*	163.20(14.9)	181.04(14.7)	0.015	0.902	1.015 [0.806 ~ 1.276]
G T*	637.80(58.2)	722.96(58.6)	0.073	0.787	0.977 [0.827 ~ 1.155]

Gastric cancer ranks as one of the prevalent malignancies affecting the gastrointestinal tract within China. This disease embodies a multifaceted pathophysiological condition, implicating an array of factors and numerous stages in its development, rendering its pathogenesis particularly intricate. Despite ongoing research, the precise mechanisms underpinning gastric cancer remain elusive. Contemporary therapeutic strategies for this cancer encompass surgical intervention, chemotherapy, and radiation therapy. Although these treatments significantly improve patients' survival rates, the prognosis is still weak, with an overall 5-year survival rate of only 30%. Therefore, specific biomarkers can help the early diagnosis, screening, and drug targeted therapy of gastric cancer. Currently, extensive research has unequivocally established a strong correlation between genetic polymorphisms and the onset and progression of gastric cancer. Among these polymorphisms, single nucleotide polymorphisms (SNPs) represent a form of mutation that has emerged as the vanguard of genetic markers, offering fresh insights into the genetic basis of this malignancy ^[21–26].

TNFRSF11B gene is a vital regulator of the dynamic balance between osteoblasts' osteogenesis and osteoclasts' bone resorption in vivo. Previous studies mostly focused on the association between genetic variation of TNFRSF11B and bone metabolism, endothelial cell dysfunction, vascular inflammation, and atherosclerosis. Shang et al.'s findings suggested that the four SNPs in TNFRSF11B (rs6993813, rs4355801, rs1032129 and rs2073618) affect femoral neck bone density in Chinese women before and after menopause ^[27]. Boroňová et al. identified a correlation between the rs3134069 polymorphism in the TNFRSF11B gene and the incidence of osteoporotic fractures in postmenopausal women in Slovakia ^[28]. Singh et al.'s findings showed that the level of osteocalcin in Serum was significantly increased in thalassemia patients with diastolic dysfunction ^[29]. The TNFRSF11B rs2073618 SNP may be associated with left ventricular hypertrophy in thalassemia patients. Wang et al. ^[30] identified that the genetic variants rs2073617G and rs3134069C within the TNFRSF11B gene could potentially elevate the risk of unfavorable short-term outcomes in patients with LAA stroke. Chung ^[31] et al.'s findings imply that the polymorphism of the TNFRSF11B gene is linked to coronary atherosclerosis in individuals afflicted with rheumatoid arthritis. In contrast, research by González points to a lack of correlation between the TNFRSF11B rs2073618 polymorphism and bone density in postmenopausal females residing in western Mexico ^[32].

As previously highlighted, an increasing number of scholars have been delving into the relationship between TNFRSF11B and cancer in recent years ^[32]. Wieser ^[33] discovered that TNFRSF11B exhibits high expression levels in ovarian cancer tissues, specifically within tumor epithelial cells and stromal cells and thought that the RANK/RANKL/OPG pathway that TNFRSF11B participates in could affect downstream mediators, leading to poor clinical outcomes of ovarian cancer. Omar et al. conducted a case-control study and found that serum levels of TNFRSF11B rs2073618 were significantly elevated in all breast cancer patients compared to the control group, suggesting that the C allele of TNFRSF11B rs2073618 may be associated with the development and progression of breast cancer ^[34]. In contrast to Omar's findings, Luo et al. reported that TNFRSF11B is expressed at lower levels in breast cancer tissues than in healthy ones, and its presence is linked to the propensity for metastasis in breast cancer. ^[35]. They concluded that TNFRSF11B might be a tumor biomarker for breast cancer patients with potential prognostic value.^[35]

Therefore, we have reason to believe that TNFRSF11B may be associated with gastric cancer. In fact, some studies also revealed the association between TNFRSF11B and gastric cancer. Wang et al.' s ^[36] findings showed that increased copy numbers of MYC and TNFRSF11B at 8Q24 are associated with gastric cancer, especially non-cardiac gastric cancer. They found that patients with an increased copy number of MYC and TNFRSF11B at 8Q24 had shorter overall survival than those with no change in copy numbers. Moreover, Luan et al. ^[13] conducted an immunohistochemical method and gene microarray to detect TNFRSF11B expression in 70 and 160 gastric cancer patients. The investigation revealed that TNFRSF11B demonstrated pronounced cytoplasmic expression in gastric cancer, correlating with an adverse prognosis. Furthermore, the study highlighted that TNFRSF11B markedly enhances cell proliferation, migration, and invasion, as well as tumorigenicity both in vivo and in vitro in gastric cancer cell lines. Also, TNFRSF11B can inhibit the apoptosis of gastric cancer cells. However, no relevant studies have studied the relationship between TNFRSF11B and gastric cancer susceptibility from the perspective of gene polymorphism. In this case-control study, we selected 577 patients with gastric cancer and 678 healthy controls to investigate the association with polymorphism of the TNFRSF11B gene rs2073618 and rs3102735 and gastric cancer susceptibility in a Chinese population. Consistent with previous studies, we are finding an association between smoking and gastric cancer, identifying smoking as an independent risk factor for this type of cancer. Contrary to prevailing consensus, the distribution of alcohol drinking did not exhibit any significant differences between the case group and the control group. In this study, it was found that the distribution frequency difference of rs3102735 CC mutated homozygote genotype was statistically significant between the gastric cancer group and the control group (P < 0.05), and rs3102735 CC mutated homozygote genotype may increase the risk of gastric cancer. The further stratified analysis revealed that the risk of gastric cancer was significantly increased in elderly patients (> 62 years old) who carried the TNFRSF11B rs3102735 CC mutated homozygous genotype. For TNFRSF11B rs2073618 polymorphism, we found no association with gastric cancer. In stratified analysis, we also found no significant relationship between TNFRSF11B rs2073618 polymorphism and gastric cancer susceptibility in different age, gender, smoking, and drinking conditions.

To our knowledge, no studies have been conducted on the association between TNFRSF11B gene polymorphism and gastric cancer susceptibility. Although our research has reached some statistically significant conclusions and found potential risk factors for gastric cancer, there are still some limitations in our study that should be noted. First, Helicobacter pylori is widely recognized as an important cause of peptic ulcer and gastric adenocarcinoma. However, due to the lack of relevant examinations in some patients for economic reasons, the clinical data was insufficient, so we did not have statistics on Helicobacter pylori infection, which led to the limitations of this study. Moreover, while a connection between the TNFRSF11B rs3102735 polymorphism and gastric cancer has been established within our research, the underlying mechanisms remain enigmatic, necessitating more in-depth exploration. Additionally, the pathogenesis of cancer is complex, often involving both gene-gene and gene-environment interactions. The polymorphism within the TNFRSF11B gene may be interrelated with other gene polymorphisms or influenced by environmental factors. It is therefore recommended that future research should delve into these interactions more thoroughly to yield additional insights into the intricate pathways of gastric cancer's pathogenesis.

Concurrently, the negative outcomes associated with the TNFRSF11B rs2073618 polymorphism observed in this study may be influenced by a series of factors. Initially, the variability in pathological classifications and stages of progression could introduce discrepancies in the findings. As delineated by the Lauren classification, gastric cancer can be categorized into intestinal, diffuse, and mixed types, each potentially exhibiting distinct expression profiles across the various pathological forms of the disease. Second, the cohort involved in our experiment might be modest in scale. To ascertain the relevance of TNFRSF11B in the genetic predisposition to gastric cancer with greater precision, it is imperative that these results are validated within larger, independent samples. Given that gastric cancer's etiology is multifactorial, encompassing genetic makeup, environmental conditions, and lifestyle choices, it is essential to conduct broader research across diverse ethnic groups and various geographical areas to corroborate the findings presented in this article.

The research was approved by the Ethics Review Committee of Jiangsu University. The ethical approval number is 20150083 and the date of ethical approval is April 27, 2015. We confirm that all studies were conducted in accordance with relevant guidelines and regulations, and we confirm that informed consent was obtained from all participants and/or their legal guardians.

Consent for publication

Written informed consent for publication was obtained from all participants.

Data availability

The data used to support the findings of this study are available from the corresponding authors upon request.

Competing interests

The authors declare that they have no conflict of interest.

Funding

Jiangsu Provincial Key Research and Development Special Fund (BE2015666), Key project fund of Jiangsu Provincial Health Commission (ZD2022052, ZD2023016); Suqian science and technology support project fund (S2022).

Authors' contributions

Xuan Tang、Dandan Gong and Zhe Dai are the co-first authors. Yu Fan, Xiaoyan Wang and Zhenjun Gao, provided direction and guidance throughout the preparation of this manuscript. Tang Xuan、Dandan Gong and Zhe Dai wrote and edited the manuscript. Hui-wen Pan finished the data analysis. Changfeng Man and Shiqi Zhang collected and prepared the related papers. All authors read and approved the final manuscript.

Acknowledgments

Not applicable.

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WITHDRAWN: Polymorphisms rs2073618 and rs3102735 in TNFRSF11B with the Susceptibility to Gastric Cancer

Status:

Version 1

Editorial Note

Abstract

Purpose

Methods

Results

Conclusion

1. Introduction

2. Materials and Methods

2.1 Research Object

2.2 The Research Method

2.3 Statistical Methods

3. Results

3.1 Primary information for gene TNFRSF11B rs2073618 and rs3102735 polymorphisms

3.2 Characteristics of the study population

3.3 Association of TNFRSF11B rs2073618 polymorphisms with gastric cancer.

3.4 Association of TNFRSF11B rs3102735 polymorphisms with gastric cancer.

3.5 Analysis of TNFRSF11B rs2073618 and rs3102735 alleles between cases and controls

3.6 Association of TNFRSF11B rs2073618 and rs3102735 polymorphisms with GC in Different Stratification Groups

3.7 Haplotype analysis

4. Discussion

Declarations

References

Additional Declarations

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