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


METHODS
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.
Institut Cochin, Université Paris Descartes-Faculté de médecine, CNRS (UMR 8104), Paris, France.
Sébastien
S
Gaujoux
Stéphane
S
Pinson
Anne-Paule
AP
Gimenez-Roqueplo
Laurence
L
Amar
Bruno
B
Ragazzon
Pierre
P
Launay
Tchao
T
Meatchi
Rossella
R
Libé
Xavier
X
Bertagna
Anne
A
Audebourg
Jessica
J
Zucman-Rossi
Frédérique
F
Tissier
Jérôme
J
Bertherat
D048868:Adaptor Proteins, Signal Transducing; D011125:Adenomatous Polyposis Coli / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000306:Adrenal Cortex Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D018268:Adrenocortical Carcinoma / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D005787:Gene Frequency; D020868:Gene Silencing / Q000502:physiology; D017491:Genes, APC; D006801:Humans; D008297:Male; D008875:Middle Aged; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C517118:AMER1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D025521:Tumor Suppressor Proteins; D051176:beta Catenin