Molecular and clinicopathological analysis of three cases of gastric juvenile polyposis.

BACKGROUND AND AIM

Juvenile polyposis (JP) is a rare disease known to be associated with mutations either in /. JP is known to often develop into malignant tumors, with a reported probability of 9-50%. However, the mechanisms of its carcinogenesis are not fully understood. We tried to elucidate the mechanisms of malignant transformation underlying this condition in three cases of gastric JP.

METHODS

We selected polyps from each patient displaying varying degrees of atypia and their nearby normal polyps and compared them using immunohistochemistry, Sanger sequencing, and loss of heterozygosity (LOH) analysis of , , and

RESULTS

Two of the three cases were suspected of having germline mutations based on their familial medical histories; the remaining case was found to have a germline mutation following preoperative genetic testing. All three cases were shown to present with both SMAD4 positive and negative areas across each lesion, with the neoplastic lesions tending to show stronger nuclear SMAD4 expression. This expression was closely associated with the LOH status; however, we also noted paradoxical SMAD4 expression in the neoplastic lesions despite the biallelic inactivation of revealed in the genetic evaluation.

CONCLUSIONS

These data suggest that strong nuclear expression of SMAD4, even when seemingly paradoxical, seems to be closely associated with dysplastic polyps in JP. Complete inactivation of was not shown to be essential for the development of dysplastic polyps in gastric JP, and other pathways seemed to be involved in the acquisition of the malignant phenotype.