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

Familial adenomatous polyposis (FAP) is an autosomal dominant condition lea ding to the development of multiple colorectal polyps and other features. I ntrafamilial variation in phenotype is known to occur in FAP; despite carry ing the same causing mutation in the APC gene, disease expression may consi derably differ in affected individuals, likely due to the existence of modi fier 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 wh ether alterations in the COX-2 gene are involved in the development of extr acolonic polyps and extragastrointestinal features. Mutational analysis usi ng single-strand conformation polymorphism (SSCP) in 130 members of a FAP f amily displaying strong phenotype variation revealed 3 polymorphic sites wi thin the coding region of the COX-2 gene. None of these allelic variants, h owever, segregated with a particular disease phenotype. In addition, expres sion analysis was performed in 31 family members with representative phenot ypes. Neither of the two polymorphisms detected within the COX-2 promoter w as 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-PC R and TaqMan). In conclusion, germline alterations in the COX-2 gene are un likely to account for the development of extracolonic disease in FAP patien ts. Int. J, Cancer 87:812-817, 2000. (C) 2000 Wiley-Liss, Inc.