Early-onset gastric cancers have a different molecular expression profile than conventional gastric cancers

Abstract

Many studies examine the molecular genetics of gastric cancer, but few look at young patients in particular and there is no comparison of molecular expression between early-onset gastric cancer (< or = 45 years old) and conventional gastric cancers. Expression of cycloxygenase-2 (COX-2) is elevated in gastric adenocarcinomas compared to non-neoplastic mucosa, and in light of studies showing reduced risk of gastric cancer in nonsteroidal anti-inflammatory drug users, we have chosen to investigate the expression of COX-2 and related molecules in 113 early-onset gastric cancers and compare it with 91 conventional gastric cancers, using tissue microarrays. These markers include molecules known to be important in conventional gastric carcinogenesis, such as E-Cadherin, p53, COX-2, Trefoil Factor-1 (TFF1), beta-catenin, p16 and c-myc; as well as molecules not yet described as being important in gastric cancer, such as the transcription factor c-jun, the COX-2 mRNA stabilizer HuR, and C/EBP-beta, a transcription factor for COX-2. All markers showed a statistically significant difference between early-onset gastric cancers and conventional gastric cancers, using a chi2 test. In particular, early-onset gastric cancers displayed a COX-2 Low, TFF1-expressing phenotype, whereas COX-2 overexpression and loss of TFF1 was found in conventional cancers, and this difference between early-onset gastric cancers and conventional cancers remained statistically significant when adjusted for location and histology (P<0.0001 and P = 0.002 respectively). We found that COX-2 overexpression correlates significantly with loss of TFF1 (P = 0.001), overexpression of C/EBP-beta (P<0.001) and cytoplasmic HuR (P = 0.016). COX-2 was significantly associated with p53 positivity (P = 0.003). Abnormalities in E-Cadherin correlated significantly with diffuse phenotype, whereas high expression of COX-2, loss of TFF1 and overexpression of C/EBP-beta correlated with the intestinal phenotype. Our results provide further evidence that early-onset gastric cancer exhibits a distinctive expression profile that may have practical implications.

The COX-2 promoter polymorphism –765 G>C is associated with early-onset, conventional and stump gastric cancers

“…Of note, 94 of the early-onset gastric cancers and 90 cases of conventional gastric cancers described in Table 3 have been published previously, 9 where a statistically significant difference (Po0.001) was seen between early-onset gastric cancer and conventional gastric cancer, with early-onset gastric cancer having a COX-2 lowexpressing phenotype as well as a statistically significant association with the intestinal phenotype (Po0.001). This statistical difference remained COX-2 promoter polymorphism -765 G4C and gastric cancers R Sitarz et al when adjusted for histology and location using a binary logistic regression model (Po0.001).…”

“…9 In 51 cases, it was performed on whole-tissue sections and in six cases tumor tissue was no longer available or unassessable on the TMA. Sections (4 mm) were deparaffinized and antigen was retrieved by 10 min of boiling in 0.01 M Na-citrate buffer (pH 6), followed by immersion in 0.03% hydrogen peroxide in methanol for 20 min.…”

“…9 The expression of COX-2 is regulated by a complex signal transduction pathway in which many nuclear proteins interact with the COX-2 promoter region and play a decisive role in gene transcription. 13 Naturally occurring singlenucleotide polymorphisms (SNPs) in the COX-2 promoter may therefore have a great impact on gene transcriptional activity by altering the binding capability with certain nuclear proteins, resulting in inter-individual variability in susceptibility to cancer and in response to the treatment of patients with COX-2 inhibitors.…”

Association between LMP2 and LMP7 gene polymorphisms and the risk of gastric cancer: A case-control study

“…Carcinogenesis is an accumulation of genetic events during aging, and the age-dependent increase in the incidence of GC demonstrates a steep slope (28). The increased risk of GC in the elderly indicates that gene-environment interactions may be involved in carcinogenesis, and the LMP7-145 genotype effects tended to be age-specific.…”

IL-1B −31T>C promoter polymorphism is associated with gastric stump cancer but not with early onset or conventional gastric cancers

“…In conventional gastric cancer (presenting >45 years old), environmental factors play a more important role, compared to early onset gastric cancer (EOGC, presenting at ≤45 years old) where it is postulated that genetic factors may be more important [20]. We have previously shown that molecular differences exist between conventional gastric cancer and EOGC [4][5][6][29][30][31][32]. Apart from cases of hereditary gastric cancer, it remains unclear what predisposes the young patients to gastric cancer at such an early age.…”