Germline alterations in the cyclooxygenase-2 gene are not associated with the development of extracolonic manifestations in a large Swiss familial adenomatous polyposis kindred

Abstract

Familial adenomatous polyposis (FAP) is an autosomal dominant condition leading to the development of multiple colorectal polyps and other features. Intrafamilial variation in phenotype is known to occur in FAP; despite carrying the same causing mutation in the APC gene, disease expression may considerably differ in affected individuals, likely due to the existence of modifier genes. Several lines of evidence suggest the cyclooxygenase‐2 (COX‐2) gene to be a candidate modifier in FAP. Since COX‐2 appears to be expressed in tissues prone to be affected in FAP, it might influence the occurrence of extracolonic manifestations in this disorder. Herein, we investigated whether alterations in the COX‐2 gene are involved in the development of extracolonic polyps and extragastrointestinal features. Mutational analysis using single‐strand conformation polymorphism (SSCP) in 130 members of a FAP family displaying strong phenotype variation revealed 3 polymorphic sites within the coding region of the COX‐2 gene. None of these allelic variants, however, segregated with a particular disease phenotype. In addition, expression analysis was performed in 31 family members with representative phenotypes. Neither of the two polymorphisms detected within the COX‐2 promoter was associated with a given phenotype nor was there a significant difference in quality or quantity of COX‐2 mRNA in lymphocytes as measured by reverse transcription‐ and real time quantitative reverse transcription PCR (RT‐PCR and TaqMan). In conclusion, germline alterations in the COX‐2 gene are unlikely to account for the development of extracolonic disease in FAP patients. Int. J. Cancer 87:812–817, 2000. © 2000 Wiley‐Liss, Inc.

Common Promoter Variant in Cyclooxygenase-2 Represses Gene Expression

“…40 The presence of other naturally occurring polymorphisms in the promoter of COX-2 has been reported; however, none have so far been shown to be functional or to be associated with inflammatory disease. 18,19 None of these changes are located within recognized transcription factor binding sites. We did not identify these changes in the present study; however, this may be due to low allele frequencies and the ethnic group studied.…”

“…We did not identify these changes in the present study; however, this may be due to low allele frequencies and the ethnic group studied. 18,19 The effect of Ϫ765GϾC and other COX-2 gene variants may have implications in the use of NSAIDs. Regular use of NSAIDs has proven effective in reducing the risk of developing diseases, in particular, cardiovascular disease and bowel cancer.…”

“…[15][16][17] Naturally occurring gene polymorphisms have been reported in COX-2; however, the functional significance of those found in the 5Ј flanking region is unclear. 18,19 We hypothesized that dysregulation of COX-2 expression has a role in COX-2-mediated pathology and that this, in part, may be due to functional changes in the 5Ј transcriptional regulatory promoter region of the gene. We report in the present study the presence of novel promoter variants in COX-2 and show that 1 of them, lying in a putative Sp1 binding site, affects the transcription rate of a reporter gene in transient transfection studies.…”

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

“…Several SNPs in COX-2 have been reported previously, but many of these polymorphisms seem to be functionally insignificant and not associated with susceptibility to cancer. [20][21][22] However, it has been shown that the À765G4C COX-2 polymorphism has been reported to disrupt an Sp1-binding site and displays a lower promoter activity, 14 and interestingly, a higher COX-2 expression has been found in the normal mucosa of patients with FAP who carried the À765GG polymorphism, 15 than carriers of the C allele. These findings awaken curiosity within the field of gastric cancer, as to whether it may also play a role here.…”

Cyclooxygenase-2 Polymorphism

“…However, a limited number of polymorphisms in the COX-2 promoter region, with potential impact on the COX-2 phenotype, have been identified. 15,16 Unfortunately, these polymorphisms were not located in any known transcription factor binding site that could potentially impact transcription, did not result in an inactive COX-2 enzyme, or change the NSAID susceptibility and the metabolite profile. Altered function of COX-2 had been hypothesized to change the number of colonic polyps in patients with an inherited predisposition to colon cancer, and two COX-2 gene sequencing studies in patients with adenomatous polyposis coli (APC) have been reported.…”