期刊
CLINICAL CANCER RESEARCH
卷 16, 期 21, 页码 5133-5141出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-10-1497
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资金
- Contrat d'Initiation a la Recherche Clinique [CIRC 05045]
- Plan Hospitalier de Recherche Clinique [AOM06179]
- Recherche Translationnelle DHOS/INCA [RTD09024]
- Fond d'Etude et de Recherche du Corps Medical (FERCM)-AP-HP, Paris, France
Purpose: In adrenocortical tumors (ACT), Wnt/beta-catenin pathway activation can be explained by beta-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-Wiede-mann syndrome with Wilms' tumors reported to have WTX somatic mutations. Both APC and WTX are involved in Wnt/beta-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 beta-catenin localization on immunohistochemistry but no somatic beta-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 beta-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/beta-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. Clin Cancer Res; 16(21); 5133-41. (C)2010 AACR.
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