Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms.

Abstract Increased Risk of Noncardia Gastric Cancer Associated With Proinflammatory Cytokine Gene Polymorphisms Dear Sir: We have read with interest the paper by El-Omar et al.1 who studied in 210 controls and 475 patients with esophageal or gastric cancer, a total of 7 single nucleotide polymorphisms (SNPs) in IL-1! (!511 C/T), IL-4 (!590 C/T), IL-6 (!174 G/C), IL-10 (!1082 G/A, !819 C/T, !592 C/A) and TNF-" (!308 G/A), demonstrating an association between the proinflammatory genotypes of IL-1! (!511 T/T) or TNF-" (!308 A/A) and the risk on noncardia gastric cancer. We studied the SNPs of IL-1! (!31 C/T) and of the promoter/enhancer region of TNF-" (!1031 C/T, !857 C/T, !376 A/G, !308 A/G and !238 A/G) by 5" nuclease polymerase chain reaction assays (TaqMan) in a total of 921 subjects, of which 129 had noncardia gastric cancer (78 males, 51 females, age range, 38–90 years), 116 duodenal ulcer (76 males, 40 females, age range, 17–78 years), 32 gastric ulcer (16 males, 16 females, age range, 26–85 years), 644 gastritis and/or duodenitis (270 males, 374 females, age range, 17–94 years). Differently from El-Omar et al.1 we assessed H. pylori infection (ureA) and its virulence genes cagA and vacA by PCR in surgical samples from patients with noncardia gastric cancer.2 In the 792 nonneoplastic patients, H. pylori infection, antral inflammation and intestinal metaplasia (positive in 222 cases) were histologically evaluated, cagA and vacA were PCR amplified from positive H. pylori colonies. H. pylori infection, cagA or s1 vacA were significantly associated with gastric or duodenal ulcer, and with noncardia gastric cancer (#2 $ 70.44, P % 0.001 for H. pylori, #2 $ 44.22, P % 0.001 for cagA and #2 $ 41.65, P % 0.001 for s1 vacA), confirming the role of H. pylori infection and of its virulence genes in causing peptic ulcer and gastric adenocarcinoma.2–4 We did not find any significant association between IL-1 !31 SNP, which is in linkage with IL-1! !511,5 and (1) diagnosis (P $ ns), (2) H. pylori infection (P $ ns), (3) H. pylori cagA (P $ ns), (4) antral inflammation (P $ ns), or (5) intestinal metaplasia (P $ ns). The discrepancy between ours and El-Omar’s results1 on the association between IL-1! genotype and noncardia gastric cancer, might be due to the genetic differences between the two studied populations, which were from Italy (our) or from the United States. TNF-" !1031 SNP was in linkage with the other TNF-" SNPs (#2 $ 60.56, P % 0.001 for !857, #2 $ 50.87, P % 0.001 for !376, #2 $ 29.17, P % 0.001 for !308, #2 $ 125.74, P % 0.001 for !238). A linkage was also found between Figure 1. Frequency of patients with duodenal ulcer (DU), noncardia gastric cancer (NCGC), or other gastroduodenal benign diseases (GDBD), bearing the TNF" !857 T/T genotype. Table 1. Association Between Antral Inflammatory Grade and TNF-" SNPs of the Promoter/Enhancer Region of the Gene TNF-" SNPs Antral inflammation Statistics Genotype Mean Range Median test TNF-" !1031 C/C 1.38 1–2 P% 0.05 C/T 1.69 0–3 T/T 1.63 0–3 TNF-" !857 C/C 1.57 0–3 P:ns C/T 1.57 0–3 T/T 1.73 1–3 TNF-" !376 A/A — — A/G 1.57 0–3 P:ns G/G 1.58 0–3 TNF-" !308 A/A 1.33 0–3 P:ns A/G 1.66 0–3 G/G 1.59 0–3 TNF-" !238 A/A — — A/G 1.53 0–3 P:ns G/G 1.58 0–3 No patient had the TNF-" !376 A/A genotype, while only 3 cases had the TNF-" !238 A/A genotype. 382 CORRESPONDENCE GASTROENTEROLOGY Vol. 126, No. 1 TNF-" !857 and !308 (#2 $ 23.88, P % 0.001) or !238 (#2 $ 13.91, P % 0.005) and between TNF-" !376 and !238 (#2 $ 363.47, P % 0.001). TNF-" !857 T/T genotype was more frequent in patients with duodenal ulcer than in those with noncardia gastric cancer or other benign diseases, considering the patients overall (#2 $ 38.78, P % 0.01) or only those H. pylori infected (#2 $ 34.65, P % 0.05) or infected by cagA positive strains (#2 $ 12.50, P % 0.05) (Figure 1). The risk of duodenal ulcer for the TNF-" !857 T/T genotype was 4.28 (95% CI, 1.80–10.21). TNF-" !857 T allele is associated with high transcriptional activity of the promoter/enhancer region.6 This might cause an enhanced mucosal release of TNF-& in response to H. pylori infection, and high mucosal levels of TNF-& has been suggested to play a pivotal role in the pathogenesis of duodenal ulcer.7 TNF-" !308 SNP was correlated with H. pylori infection (#2 $ 9.70, P % 0.05), which was more frequent in TNF-" !308 A/G (61.2%) than in G/G (54.1%) subjects, in agreement with previous data by Yea et al.8 in Korean patients. Antral inflammation was more severe in patients bearing TNF " !1031 T allele (#2 $ 12.3, P % 0.05) (Table 1). The presence or absence of intestinal metaplasia was not correlated with any of the studied cytokines’ SNPs, but it was correlated with H. pylori antral density grade (#2 $ 10.59, P % 0.05) and with cagA (Fisher exact test, P % 0.001) or s1 vacA (Fisher exact test, P % 0.001). We suggest that TNF-" !308 and !1031 SNPs might be involved in favoring H. pylori infection and the inflammatory response of the infected gastric mucosa. TNF-" !857 T/T genotype might predispose to duodenal ulcer. TNF" SNPs in the promoter/enhancer region of the gene, do not seem involved in favoring the precancerous intestinal metaplasia or noncardia gastric cancer. CARLO-FEDERICO ZAMBON DANIELA BASSO FILIPPO NAVAGLIA ALESSANDRA FALDA CLAUDIO BELLUCO PAOLA FOGAR ELIANA GRECO NICOLETTA GALLO FABIO FARINATI ROMILDA CARDIN MASSIMO RUGGE FRANCESCO DI MARIO MARIO PLEBANI Departments of Medical and Surgical Sciences, Laboratory Medicine, Oncological and Surgical Sciences, Gastroenterology, and Pathology University of Padova Padova, Italy Department of Gastroenterology University of Parma Parma, Italy 1. El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, Schoenberg JB, Stanford JL, Mayne ST, Goedert J, Blot WJ, Fraumeni JF Jr, Chow W-H. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 2003;124:1193–1201. 2. Basso D, Navaglia F, Brigato L, Piva MG, Toma A, Greco E, DiMario F, Galeotti F, Roveroni G, Corsini A, Plebani M. Analysis of Helicobacter pylori vacA and cagA genotypes and serum antibody profile in benign and malignant gastroduodenal diseases. Gut 1998;43:182–186. 3. Zambon C-F, Basso D, Navaglia F, Germano G, Gallo N, Milazzo M, Greco E, Fogar P, Mazza S, Di Mario F, Basso G, Rugge M, Plebani M. Helicobacter pylori virulence genes and host IL-1RN and IL- 1beta genes interplay in favouring the development of peptic ulcer and intestinal metaplasia. Cytokine 2002;18:242–251. 4. Montecucco C, Rappuoli R. Living dangerously: how Helicobacter pylori survives in the human stomach Nature Rev Mol Cell Biol 2001;2:457–466. 5. El-Omar EM, Carrington M, Chow W-H, McColl KEL, Bream JH, Young HA, Herrera J, Lissowska J, Yuan C-C, Rothman N, Lanyon G, Martin M, Fraumeni JF Jr, Rabkin CS. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 2000;404:398–402. 6. Tsukasaki K, Miller CW, Kubota T, Takeuchi S, Fujimoto T, Ikeda S, Tomonaga M, Koeffler HP. Tumor necrosis factor alpha polymorphism associated with increased susceptibility to development of adult T-cell leukemia/lymphoma in human T-lymphotropic virus type 1 carriers. Cancer Res 2001;61:3770–3774. 7. Alkout AM, Blackwell CC, Weir DM. Increased inflammatory responses of persons of blood group O to Helicobacter pylori. J Infect Dis 2000;181:1364–1369. 8. Yea SS, Yang Y-I, Jang WH, Lee YJ, Bae H-S, Paik K-H. Association between TNF-& promoter polymorphism and Helicobacter pylori cagA subtype infection. J Clin Pathol 2001;54:703–706. doi:10.1053/j.gastro.2003.08.042 Reply. We thank Zambon et al. for their interest in our paper and for sharing their data. Their study, comprising a heterogeneous group of upper gastrointestinal pathologies and including 129 gastric cancer cases, failed to find statistically significant associations between IL- 1B-31 and TNFA-308 proinflammatory genotypes and gastric cancer or its precursors. However, their findings are at odds with a number of larger studies that have looked at these important markers. For example, there were 366 gastric cancer cases vs. 429 population controls in our earlier study based in Poland,1 and this was confirmed in our U.S. study with 188 cases and 210 controls.2 Machado et al. independently confirmed both IL-1B-5113,4 and TNFA-308 findings in a study of 287 gastric cancer cases vs. 306 controls.5 Furthermore, Rad et al.6 and Furuta et al.7 confirmed the association between IL-1 markers and gastric premalignant abnormalities in Caucasian and Japanese populations, respectively. We found it difficult to analyze or comment on the other findings in the study by Zambon et al. due to the lack of subject details and restriction of statistical data to #2 and P values. We also caution about their reported associations with the TNFA SNP’s –1031 and -857 pending better definition of the functional significance of these genetic markers. Nevertheless, we agree with Zambon et al. about the important role of cytokine gene polymorphisms in the pathogenesis of H. pylori-related diseases. EMAD M. EL-OMAR Department of Medicine and Therapeutics Aberdeen University Aberdeen, Scotland CHARLES S. RABKIN WONG-HO CHOW Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda, Maryland 1. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni JF Jr, Rabkin CS. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 2000;404: 398–402. 2. El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, January