Inactivation of the APC gene is constant in adrenocortical tumors from patients with familial adenomatous polyposis but not frequent in sporadic adrenocortical cancers.

PURPOSE: In adrenocortical tumors (ACT), Wnt/ß-catenin pathway activation can be explained by ß-catenin somatic mutations only in a subset of tumors. ACT is observed in patients with familial adenomatous polyposis (FAP) with germline APC mutations, as well as in patients with Beckwith-Wiedemann syndrome with Wilms' tumors reported to have WTX somatic mutations. Both APC and WTX are involved in Wnt/ß-catenin pathway regulation and may play a role in ACT tumorigenesis. The aim of this study was to report if APC and WTX may be associated with FAP-associated and sporadic ACT. EXPERIMENTAL DESIGN: ACTs from patients with FAP and sporadic adrenocortical carcinomas (ACC) with abnormal ß-catenin localization on immunohistochemistry but no somatic ß-catenin mutations were studied. APC was analyzed by denaturing high-performance liquid chromatography followed by direct sequencing and by multiplex ligation-dependent probe amplification when allelic loss was suspected. WTX was studied by direct sequencing. RESULTS: Four ACTs were observed in three patients with FAP and were ACC, adrenocortical adenoma, and bilateral macronodular adrenocortical hyperplasia, all with abnormal ß-catenin localization. Biallelic inactivation of APC was strongly suggested by the simultaneous existence of somatic and germline alterations in all ACTs. In the 20 sporadic ACCs, a silent heterozygous somatic mutation as well as a rare heterozygous polymorphism in APC was found. No WTX mutations were observed. CONCLUSIONS: ACT should be considered a FAP tumor. Biallelic APC inactivation mediates activation of the Wnt/ß-catenin pathway in the ACTs of patients with FAP. In contrast, APC and WTX genetic alterations do not play a significant role in sporadic ACC.