Functional promoter polymorphisms of NFKB1 influence susceptibility to the diffuse type of gastric cancer

Abstract

Abstract. In the present study, we report an association between gastric cancer and polymorphisms in NFKB1 (rs28362941 and rs78696119). We employed the PCR-SSCP method to detect gene polymorphisms in 479 gastric cancer cases and 880 controls. The rs28362941 del/del homozygote was significantly associated with gastric cancer development; in particular it was closely associated with diffuse type gastric cancer. The rs78696119 GG homozygote was also associated with the diffuse type of gastric cancer. In young subjects, both polymorphisms were significantly associated with the development of gastric cancer. In addition, both polymorphisms were related to tumor progression such as tumor invasion and lymph node metastasis. The inflammatory cell infiltration into non-cancerous gastric mucosa was greater in the subjects with the rs28362491 del/del or rs78696119 GG genotype when compared to those with the other genotypes. In conclusion, functional polymorphisms of NFKB1 are associated with an increased risk of gastric cancer; in particular they are closely associated with the development of diffuse type of gastric cancer via severe gastric inflammation. These polymorphisms also appear to be associated with gastric cancer progression.

Endogenous glucocorticoids prevent gastric metaplasia by suppressing spontaneous inflammation

“…For instance, CagA + strains of H. pylori elicit more robust inflammation and are associated with a higher incidence of cancer (50,51). Furthermore, polymorphisms in genes encoding the inflammatory mediators IL1B or NFKB1 dramatically increase the risk of gastric cancer in H. pylori-infected individuals (9,52,53), and can even promote cancer development in the absence of infection (6)(7)(8). Here we demonstrate that signaling by endogenous glucocorticoids is required to suppress pathogenic gastric inflammation metaplasia.…”

“…Mice overexpressing the proinflammatory cytokines IL1B or IFNG in parietal cells, or that have dysregulated NFKB activity, exhibit spontaneous gastric inflammation leading to metaplasia and gastric cancer (6)(7)(8). In humans, polymorphisms in the IL1B or NFKB1 genes are linked to gastric cancer development, even in the absence of H. pylori infection (9,10). However, the molecular and cellular processes that regulate gastric inflammation and the mechanisms whereby the inflammatory milieu promotes metaplastic changes are poorly understood.…”

Interactions between inflammatory gene polymorphisms and HTLV-I infection for total death, incidence of cancer, and atherosclerosis-related diseases among the Japanese population

“…The associations between inflammatory gene polymorphisms and the development of ATLL 23 and HAM/TSP has been reported. 24 , 25 , 26 , 27 Interestingly, these polymorphisms were also associated with the development of not only several sites of cancer, 28 , 29 , 30 , 31 , 32 , 33 but also atherosclerosis-related diseases. 34 , 35 , 36 , 37 TNF- α , encoded by the TNF -α gene, is a cytokine responsible for resistance to infection and cancers and exerts major proinflammatory action by stimulating adhesion molecules and chemokine expression.…”

“…We selected three single-nucleotide polymorphisms (SNPs) with minor allele frequencies (MAF) greater than 0.05 from the common genes for cytokines that have important roles in the immune-inflammatory processes of HTLV-I infection, cancers, and atherosclerosis, including TNF -α 1031T/C [rs1799964], IL-10 819T/C [rs1800871], and NF- κ B1 94ATTG ins/del [rs28362491]. 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 These SNPs were genotyped using TaqMan allelic discrimination kits (Applied Biosystems, Foster City, CA, USA) and real-time polymerase chain reaction (StepOne, Applied Biosystems). Each reaction was performed in a 10 μL volume that contained 1 μL of genomic DNA (10 mg/μL), 5 μL of TaqMan Universal PCR Master Mix II, 0.125 μL of 40 × genotyping assay mix, and 3.875 μL of dH 2 O.…”

NF‐κB Signaling in Gastric Cancer

“…Recently, Arisawa et al [145] demonstrated that the rs28362941 del/del and the rs78696119 GG homozygotes were associated with the diffuse type of gastric cancer, especially in young subjects. In addition, both NF κ B1/p50 promoter variants were associated with tumor progression such as tumor invasion and lymph node metastasis, in comparison to other genotypes.…”