Related Experiment Videos
Molecular analysis of sulindac-resistant adenomas in familial adenomatous polyposis
J J Keller1, G J Offerhaus, P Drillenburg
1Department of Pathology, Academic Medical Center, 1100 DD Amsterdam, the Netherlands. j.j.keller@amc.uva.nl
Purpose:
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).
Design:
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.
Insights
Familial adenomatous polyposis (FAP) patients resistant to sulindac show fewer changes in beta-catenin and epithelial Cox-2 expression. K-ras mutations may drive this sulindac resistance in FAP adenomas.
Area of Science:
- Gastroenterology
- Oncology
- Molecular Biology
Background:
- Sulindac reduces adenomas in familial adenomatous polyposis (FAP) but complete regression is rare.
- Breakthrough colorectal carcinoma during sulindac treatment has been observed.
- Molecular mechanisms underlying sulindac resistance in FAP remain unclear.
Purpose of the Study:
- To investigate molecular alterations in FAP adenomas from patients with complete regression (responsive) versus those with resistant adenomas.
- To identify potential biomarkers associated with sulindac resistance in FAP.
Main Methods:
- Immunohistochemistry was used to assess beta-catenin, cyclooxygenase-2 (Cox-2), p53, Bcl-2, and Bax expression.
- PCR-based techniques analyzed K-ras codon 12 mutations, 5q loss of heterozygosity (APC locus), and microsatellite instability.
- Adenomas from responsive and resistant FAP patients, both baseline and during treatment, were analyzed.
Main Results:
- Resistant adenomas showed less loss of membranous beta-catenin and less nuclear beta-catenin accumulation compared to baseline adenomas.
- Epithelial Cox-2 expression was significantly lower in baseline adenomas from responsive patients compared to resistant patients.
- K-ras mutations were detected in 24% of resistant adenomas but none of the baseline adenomas, suggesting a role in resistance.
Conclusions:
- Sulindac-resistant FAP adenomas exhibit reduced alterations in beta-catenin staining and lower epithelial Cox-2 expression.
- K-ras mutations are implicated as a potential factor contributing to sulindac resistance in FAP.
- Further research is warranted to fully elucidate the molecular pathways of sulindac resistance.