title: The inducible prostaglandin biosynthetic enzyme, cyclooxygenase 2, is not mutated in patients with attenuated adenomatous polyposis coli.
abstract: Germ-line mutations in the APC gene cause adenomatous polyposis coli (APC), a syndrome in which patients develop hundreds to thousands of precancerous adenomatous colorectal polyps. We described previously an attenuated form of APC (AAPC) resulting from very 5' mutations in APC in which affected patients exhibit fewer colorectal polyps and a later age of onset of colorectal cancer. However, because striking variations in colorectal polyp numbers occur among patients carrying identical AAPC mutations, alleles of another gene may modify the expression of the APC disease phenotype. We tested the hypothesis that loss of function of human cyclooxygenase 2 (COX-2), known to modify the APC phenotype in the Apc delta716 mouse, results in a decreased tumor burden in AAPC patients that develop very few colorectal polyps. Genomic DNA sequence analysis of human COX-2 revealed a silent mutation in exon 3 that was evenly distributed between two classes of patients with AAPC, those with small or large numbers of colorectal polyps. We also found no difference in levels of COX-2 mRNA in transformed blood lymphocytes among AAPC patients of either class or patients with classical APC, and no alterations that correlated with a lesser or greater number of colorectal polyps were detectable within approximately the first 1 kb of the promoter sequence. Therefore, mutation of the human COX-2 gene does not appear to be responsible for a low tumor burden among AAPC subjects.
authors.affiliation: Department of Oncological Sciences and the Huntsman Cancer Institute, Salt Lake City, Utah 84112-5330, USA.
authors.forename: L N
authors.initials: LN
authors.lastname: Spirio
authors.forename: D A
authors.initials: DA
authors.lastname: Dixon
authors.forename: J
authors.initials: J
authors.lastname: Robertson
authors.forename: M
authors.initials: M
authors.lastname: Robertson
authors.forename: J
authors.initials: J
authors.lastname: Barrows
authors.forename: E
authors.initials: E
authors.lastname: Traer
authors.forename: R W
authors.initials: RW
authors.lastname: Burt
authors.forename: M F
authors.initials: MF
authors.lastname: Leppert
authors.forename: R
authors.initials: R
authors.lastname: White
authors.forename: S M
authors.initials: SM
authors.lastname: Prescott
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000201:enzymology* / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D051545:Cyclooxygenase 1; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008565:Membrane Proteins; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse