Molecular analysis of sulindac-resistant adenomas in familial adenomatous polyposis.
OBJECTIVE
Sulindac causes the reduction of adenomas in familial adenomatous polyposis (FAP) patients, but complete regression is unusual, and breakthrough of colorectal carcinoma during sulindac treatment has been described. The molecular features related to sulindac resistance are unknown. Therefore, we investigated molecular alterations in adenomas from FAP patients with complete adenoma regression on sulindac (responsive patients) and from FAP patients with sulindac-resistant adenomas (resistant patients).


METHODS
Fourteen baseline adenomas (removed before sulindac treatment) from six responsive patients were studied. Also, 9 baseline adenomas and 34 resistant adenomas (removed during sulindac treatment) from three resistant patients were analyzed. Using immunohistochemistry, we evaluated the expression of beta-catenin, cyclooxygenase-2 (Cox-2), p53, Bcl-2, and Bax. K-ras codon 12 mutations, loss of heterozygosity at 5q (APC locus), and microsatellite instability were studied with PCR-based techniques.


RESULTS
There were no significant differences between baseline adenomas from sulindac-responsive and -resistant patients (P > 0.05). There was less loss of membranous beta-catenin staining and less nuclear beta-catenin accumulation in resistant adenomas compared with baseline adenomas from the same (sulindac-resistant) patients (P < 0.01) or baseline adenomas from responsive patients (P < 0.01). Epithelial Cox-2 expression was less, though not significant, in resistant adenomas compared with baseline adenomas from resistant patients, but was significantly less in baseline adenomas from responsive patients (P < 0.01). K-ras mutations were found in 8 of 34 resistant adenomas (24%) and in none of the baseline adenomas (P < 0.05). Stromal Cox-2 expression, staining of p53 and Bcl-2, and loss of heterozygosity at 5q were comparable in both groups. Loss of Bax staining and microsatellite instability were not found in any adenoma.


CONCLUSIONS
Sulindac-resistant adenomas display less alteration in beta-catenin staining and less epithelial Cox-2 expression when compared with adenomas removed before sulindac treatment. K-ras mutations may contribute to sulindac-resistance. Continued research is needed to investigate molecular alterations related to sulindac resistance.
Keller
J J
JJ
Department of Pathology, Academic Medical Center, 1100 DD Amsterdam, the Netherlands. j.j.keller@amc.uva.nl
Offerhaus
G J
GJ
Drillenburg
P
P
Caspers
E
E
Musler
A
A
Ristimäki
A
A
Giardiello
F M
FM
D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis; D003062:Codon; D051546:Cyclooxygenase 2; D003598:Cytoskeletal Proteins / Q000032:analysis; D019008:Drug Resistance, Neoplasm; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis; D019656:Loss of Heterozygosity; D008565:Membrane Proteins; D009154:Mutation; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012004:Rectal Neoplasms / Q000188:drug therapy; D013467:Sulindac / Q000627:therapeutic use*; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D051028:bcl-2-Associated X Protein; D051176:beta Catenin
D000970:Antineoplastic Agents; C494826:BAX protein, human; D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D003062:Codon; D003598:Cytoskeletal Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051176:beta Catenin; D013467:Sulindac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases