Cyclooxygenase-2 expression in polyps from a patient with juvenile polyposis syndrome with mutant BMPR1A.
OBJECTIVE
Cyclooxygenase-2 (COX-2) expression is increased in colorectal cancers and has been reported to be upregulated in Peutz-Jeghers polyps. To determine whether germline and somatic loss of BMPR1A in polyps from a patient with juvenile polyposis syndrome have altered COX-2 expression, we characterized a patient with juvenile polyposis syndrome for BMPR1A germline mutations and examined the polyps for BMPR1A expression and COX-2 expression.


METHODS
DNA analysis for BMPR1A was performed on a patient with juvenile polyposis syndrome. Multiple polypectomies were performed, and several polyps showed adenomatous change. Genomic DNA was extracted from polyp material for loss of heterozygosity (LOH) analyses with microsatellite markers. Immunohistochemistry was performed on sections using antibodies for BMPR1A and COX-2.


RESULTS
The kindred possessed a germline BMPR1A missense mutation. In polyp domains containing cystic and adenomatous epithelium, no LOH was observed using markers near the BMPR1A locus. Immunostaining indicated decreased expression of phospho-SMAD1 (pSMAD1), functionally downstream of the mutant BMPR1A receptor in the cystic epithelium, with further reduction in adenomatous portions within the polyp. COX-2 protein, normally not expressed in the colon, was present and increased in polyp epithelium.


CONCLUSIONS
Decreased expression of pSMAD1 in the cystic epithelium with further reduction in the adenomatous area, and increase in COX-2 expression within polyps from the BMPR1A heterozygote, suggest a potential mechanism for adenomatous pathogenesis in these hamartomatous polyps. This may imply that COX-2 inhibitors could be a means for chemoprevention in this syndrome.
Kurland
Jayde E
JE
Department of Medicine, Naval Medical Center, San Diego, CA, USA.
Beck
Stayce E
SE
Solomon
Carol J
CJ
Brann
Oscar S
OS
Carethers
John M
JM
Huang
Sherry C
SC
D000328:Adult; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000096:biosynthesis / Q000235:genetics*; D003110:Colonic Neoplasms / Q000209:etiology; D003111:Colonic Polyps / Q000150:complications / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010580:Peutz-Jeghers Syndrome / Q000235:genetics*; D051898:Smad1 Protein / Q000096:biosynthesis
D051898:Smad1 Protein; D051546:Cyclooxygenase 2; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I