Inactivation of theAPCGene Is Constant in Adrenocortical Tumors from Patients with Familial Adenomatous Polyposis but Not Frequent in Sporadic Adrenocortical Cancers

Abstract

Purpose: In adrenocortical tumors (ACT), Wnt/β-catenin pathway activation can be explained by β-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/β-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 β-catenin localization on immunohistochemistry but no somatic β-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 β-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/β-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. ©2010 AACR.

Genetics of primary macronodular adrenal hyperplasia

“…These lesions usually reveal a bi-allelic inactivation of APC, namely, the presence of germinal and somatic mutations in adrenal tissue, in accordance with the proposed Knudson model (Blaker et al 2004, Hosogi et al 2009, Gaujoux et al 2010, Berthon et al 2012. In a previous study, only one patient with familial adenomatous polyposis and PMAH failed to display LOH of APC in adrenal hyperplasia (Yamakita et al 1997).…”

“…Colorectal carcinomas develop with progression of the disease, and have an incidence of nearly 100% after 40 years in the absence of adequate treatment (Groen et al 2008, Hosogi et al 2009). Certain intestinal manifestations occur more frequently in individuals with familial APC, such as papillary thyroid carcinomas, hepatoblastomas, brain tumors, pancreatic carcinomas, adrenocortical lesions, desmoid tumors, osteomas, epidermoid cysts, fibromas, lipomas, and congenital hypertrophy of the retinal pigment epithelium (Gaujoux et al 2010).…”

Long-term study of subclinical Cushing^|^rsquo;s syndrome shows high prevalence of extra-adrenal malignancy in patients with functioning bilateral adrenal tumors

“…Mutations of genes that encode G-protein subunit α, type 1α regulatory subunit of cAMP-dependent PKA, and phosphodiesterases type 11A and type 8B have also been identified in adrenocortical adenoma or hyperplasia [26][27][28][29]. Activation of the Wnt/β-catenin signaling pathway has been shown to affect adrenocortical tumorigenesis [30][31][32]. Moreover, mutations of tumor suppressor genes such as p53, MEN1 and ARMC5 have been observed in adrenocortical adenoma or hyperplasia [24,33,34].…”

Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

“…Patients with familial adenomatous polyposis (FAP) (OMIM #175100) present multiple colonic polyps and an increased risk of early colon carcinomas and various adrenocortical tumors, including non-functional cortisol producing adenoma, adrenocortical cancer (31) and bilateral macronodular adrenal hyperplasia (10,32). FAP is caused by germline inactivating mutation of APC (5q22), a tumor suppressor gene that inhibits Wnt/ b-catenin signaling.…”

“…3A). Interestingly, the second event differs in function of the nodules in the patient with PBMAH (32). The role of the activation of b-catenin as a driver of adrenocortical tumorigenesis has been clearly demonstrated in vitro and in vivo (31).…”