Duodenal mucosal risk markers in patients with familial adenomatous polyposis: effects of celecoxib/ursodeoxycholic acid co-treatment and comparison with patient controls.
BACKGROUND
Familial adenomatous polyposis (FAP) is a disease characterized by the development of hundreds to thousands of adenomatous polyps in the colorectum early in life. Virtually all patients with FAP will develop colorectal cancer before the age of 40 to 50 years, unless prophylactic colectomy is performed, which significantly improves their prognosis. The mortality pattern has changed and duodenal cancer now is one of the main cancer-related causes of death in these patients. Practically all patients with FAP develop premalignant duodenal adenomas, which may develop to duodenal cancer in approximately 3-7% of patients. Duodenal cancer in patients with FAP has a poor prognosis. The clinical challenge is to identify patients at high-risk for duodenal carcinoma. Chemoprevention would be desirable to avoid duodenectomy. The main goal of this study is to identify risk markers in normal duodenal mucosa of patients with FAP, that could help identify patients at increased risk for malignant transformation.


METHODS
Messenger RNA (mRNA) levels of glutathione S-transferase A1 (GSTA1), glutathione S-transferase P1 (GSTP1), KIAA1199, E-cadherin, peroxisome proliferative activated receptor δ (PPARδ), caspase-3, cyclin D1, β-catenin, and cyclooxygenase-2 (COX-2) were measured in duodenal mucosa, using the QuantiGene 2.0 Plex assay. Levels in normal appearing mucosa of patients with FAP (n = 37) were compared with levels in non-FAP patient controls (n = 16). In addition, levels before and after treatment with either celecoxib & ursodeoxycholic acid (UDCA, n = 14) or celecoxib & placebo (n = 13) were evaluated in patients with FAP.


RESULTS
mRNA levels of glutathione S-transferase A1 (28.16% vs. 38.24%, p = 0.008) and caspase-3 (3.30% vs. 5.31%, p = 0.001) were significantly lower in patients with FAP vs. non-FAP patient controls, respectively. COX-2 mRNA levels in normal duodenal mucosa of patients with FAP were found to be unexpectedly low. None of the potential risk markers was influenced by celecoxib or celecoxib & UDCA.


CONCLUSIONS
Protection against toxins and carcinogens (GSTA1) and apoptosis (caspase-3) is low in patients with FAP, which could contribute to increased susceptibility for malignant transformation of duodenal mucosa.


BACKGROUND
http://ClinicalTrials.gov number NCT00808743.
Department of Gastroenterology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. w.peters@mdl.umcn.nl.
Bjorn W H
BW
van Heumen
Hennie M J
HM
Roelofs
René H M
RH
te Morsche
Fokko M
FM
Nagengast
Wilbert H M
WH
Peters
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000328:Adult; D000368:Aged; D015820:Cadherins / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000235:genetics; D004379:Duodenal Neoplasms / Q000139:chemically induced / Q000235:genetics; D005260:Female; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D006821:Hyaluronoglucosaminidase; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000235:genetics; D011720:Pyrazoles / Q000009:adverse effects* / Q000627:therapeutic use; D013449:Sulfonamides / Q000009:adverse effects* / Q000627:therapeutic use; D014580:Ursodeoxycholic Acid / Q000009:adverse effects* / Q000627:therapeutic use; D055815:Young Adult
D015820:Cadherins; D011506:Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D014580:Ursodeoxycholic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C484555:GSTA1 protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C491433:CEMIP protein, human; D006821:Hyaluronoglucosaminidase; D053148:Caspase 3; D000068579:Celecoxib