Early-onset gastric cancers have a different molecular expression profile than conventional gastric cancers.
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.
Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. a.n.milne@amc.uva.nl
Anya N A
AN
Milne
Ralph
R
Carvalho
Folkert M
FM
Morsink
Alex R
AR
Musler
Wendy W J
WW
de Leng
Ari
A
Ristimäki
G Johan A
GJ
Offerhaus
D000328:Adult; D017668:Age of Onset; D000954:Antigens, Surface / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000032:analysis; D015820:Cadherins / Q000032:analysis; D016009:Chi-Square Distribution; D051546:Cyclooxygenase 2 / Q000032:analysis; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D020598:Proto-Oncogene Proteins c-myb / Q000032:analysis; D016601:RNA-Binding Proteins / Q000032:analysis; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology*; D000071163:Trefoil Factor-1; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis; D051176:beta Catenin / Q000032:analysis
D000954:Antigens, Surface; D014408:Biomarkers, Tumor; D022782:CCAAT-Enhancer-Binding Protein-beta; D015820:Cadherins; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D008565:Membrane Proteins; D020598:Proto-Oncogene Proteins c-myb; D016601:RNA-Binding Proteins; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human