Low prevalence of loss of heterozygosity and SMAD4 mutations in sporadic and familial juvenile polyposis syndrome-associated juvenile polyps.

Background: Juvenile polyps (JP) may develop sporadically or may be associated with the familial juvenile polyposis syndrome (FJPS). In FJPS, the epithelium is susceptible to dysplasia and, ultimately adenocarcinoma. However, the mechanisms involved in this transformation are unknown. Since the epithelium in colorectal carcinogenesis undergoes a stepwise genetic progression, the purpose of this study was to determine if loss of heterozygosity (LOH) abnormalities can aid in the differentiation between sporadic and FJPS-associated polyps.

Design: Ninety-one routinely-processed JP from three groups of patients were evaluated for this study. Group 1 included 39 polyps from 39 patients with a single JP and no personal or family history of FJPS; group 2 consisted of 24 polyps from 15 patients with 2-5 JP and no history of FJPS; and group 3 included 29 polyps from 22 patients with > or =5 polyps either with (7) or without (15) a family history of FJPS. Epithelium from typical, atypical, and overtly dysplastic polyps, when present (2 cases in group 3 only), were evaluated separately by microdissection and PCR analysis for LOH of APC, p53, 3p, 9p, and mutations in exon 9 of the SMAD4 gene.

Results: SMAD4 mutations were observed in 3 polyps from 2 patients in group 3 (10% of informative cases; p < 0.05 vs group 1), but not in any of the polyps from the other two groups. Overall, LOH of APC, p53, 3p, and 9p were detected in 1%, 15%, 10%, and 4% of JPs, but no differences were observed between the three clinical groups. Two polyps, both in group 3, with definite dysplasia did not show any genetic alterations. The morphologic appearance of the polyps was not a reliable feature in helping to differentiate sporadic from FJPS-associated polyps.

Conclusions: LOH of APC, p53, 3p, and 9p may not be involved in the carcinogenic pathway of FJPS-associated polyps. SMAD4 gene mutations show a low sensitivity but a high specificity for FJPS.