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ABSTRACT: Infantile and childhood hepatoblastoma (HB) occurs more frequently in children with hereditary predisposition to familial adenomatous polyposis (FAP) than in the general population. The occurrence of HB in two infant siblings is reported. The sister died of the disease. The brother survived the HB and was later diagnosed with familial adenomatous polyposis and advanced rectal cancer. He was found to carry a germline mutation of the APC gene. Presuming that the HB in the two siblings was the first manifestation of FAP we performed APC mutation analysis in DNA from archived tumour tissue of his sister and in blood samples of both parents. Surprisingly, the mutation was neither found in both parents, nor in the tissue samples of the sister. We outline the impact of this finding for genetic counselling and review the literature on FAP and HB.
Familial Cancer 06/2012; · 1.30 Impact Factor
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ABSTRACT: Germline deletions affecting the epithelial cell adhesion molecule (EPCAM) gene lead to silencing of MSH2 and cause Lynch syndrome. We have recently reported that lack of EPCAM expression occurs in many, but not all tumors from Lynch syndrome patients with EPCAM germline deletions. The differences in EPCAM expression were not related to the localization of EPCAM germline deletions. We therefore hypothesized that the type of the second somatic hit, which leads to MSH2 inactivation during tumor development, determines EPCAM expression in the tumor cells. To test this hypothesis and to evaluate whether lack of EPCAM expression can already be detected in Lynch syndrome-associated adenomas, we analyzed four carcinomas and two adenomas from EPCAM germline deletion carriers for EPCAM protein expression and allelic deletion status of the EPCAM gene region by multiplex ligation-dependent probe amplification. In four out of six tumors we observed lack of EPCAM expression accompanied by biallelic deletions affecting the EPCAM gene. In contrast, monoallelic retention of the EPCAM gene was observed in the remaining two tumors with retained EPCAM protein expression. These results demonstrate that EPCAM expression in tumors from EPCAM deletion carriers depends on the localization of the second somatic hit that inactivates MSH2. Moreover, we report lack of EPCAM protein expression in a colorectal adenoma, suggesting that EPCAM immunohistochemistry may detect EPCAM germline deletions already at a precancerous stage.
Modern Pathology 03/2012; 25(6):911-6. · 4.79 Impact Factor
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ABSTRACT: Mutations of the cyclic nucleotide binding domain (CNBD) may disrupt human ether-a-go-go-related gene (hERG) K(+) channel function and lead to hereditary long QT syndrome (LQTS). We identified a novel missense mutation located in close proximity to the CNBD, hERG R744P, in a patient presenting with recurrent syncope and aborted cardiac death triggered by sudden auditory stimuli. Functional properties of wild type (WT) and mutant hERG R744P subunits were studied in Xenopus laevis oocytes using two-electrode voltage clamp electrophysiology and Western blot analysis. HERG R744P channels exhibited reduced activating currents compared to hERG WT (1.48±0.26 versus 3.40±0.29μA; n=40). These findings were confirmed by tail current analysis (hERG R744P, 0.53±0.07μA; hERG WT, 0.97±0.06μA; n=40). Cell surface trafficking of hERG R744P protein subunits was not impaired. To simulate the autosomal-dominant inheritance associated with LQTS, WT and R744P subunits were co-expressed in equimolar ratio. Mean activating and tail currents were reduced by 32% and 25% compared to hERG WT (n=40), indicating that R744P protein did not exert dominant-negative effects on WT channels. The half-maximal activation voltage was not significantly affected by the R744P mutation. This study highlights the significance of in vitro testing to provide mechanistic evidence for pathogenicity of mutations identified in LQTS. The functional defect associated with hERG R744P serves as molecular basis for LQTS in the index patient.
Biochemical and Biophysical Research Communications 02/2012; 418(4):830-5. · 2.48 Impact Factor
