Analysis of β-Catenin Mutations and α-, β-, and γ-Catenin Expression in Normal and Neoplastic Human Pituitary Tissues
ABSTRACT The cadherin-catenin system mediates Ca2+-dependent cell-cell adhesion, and genetic alterations in these molecules play a significant role in multistage carcinogenesis.
Mutations in the β-catenin gene, mostly affecting exon 3, have been detected in malignant cell lines and in primary tumors.
Immunohistochemical abnormalities in α-, β-, and γ-catenin have been reported in malignant and benign tumors, and nuclear
localization of β-catenin has been associated with mutations in exon 3 of this gene.
Mutational analysis of exon 3 of the β-catenin gene was undertaken by polymerase chain reaction (PCR) and sequencing using
genomic DNA extracted from frozen tissues, including 4 normal pituitaries, 22 pituitary adenomas, and one pituitary carcinoma.
Frozen sections from these cases were used for immunohistochemical detection of β-catenin. We also analyzed immunohistochemical
expression of α-, β-, and γ-catenin by paraffin sections from 154 pituitary tumors, including 148 adenomas and 6 carcinomas.
Genomic DNA was extracted from paraffin sections of 2 gonadotroph tumors showing nuclear staining for β-catenin and was used
for PCR and sequencing of exon 3 of the β-catenin gene.
No mutations in exon 3 of the β-catenin gene were found in any of the 23 cases analyzed by PCR and sequencing. In addition,
the 2 cases studied by paraffin section immunohistochemistry, with nuclear staining for β-catenin, were negative for mutations
in this exon. Normal pituitary expressed all three catenin proteins. Immunostaining usually showed a membranous pattern of
reactivity and was generally stronger in normal pituitary than in the adjacent adenomas. Stains for α-catenin were positive
in fewer tumors than for β-catenin. The lowest frequency immunopositive tumors and the weakest immunostaining was for γ-catenin.
All medically treated prolactinomas were negative for γ-catenin, whereas treated growth hormone adenomas were less often positive
for both α- and γ-catenin than for untreated tumors. The percentage of positive cases for β-catenin was the same in these
two groups. Most pituitary carcinomas were negative for both α- and γ-catenin but were β-catenin positive.
These results indicate that (i) mutations in exon 3 of the β-catenin gene are uncommon in pituitary tumors, and (ii) expression of α-, β-, and γ-catenin is decreased in pituitary adenomas compared to normal pituitary tissues.
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ABSTRACT: The cadherin-catenin complex regulates cellular adhesion and motility, and genetic alterations in these molecules play a critical role in multistage tumorigenesis. In this study, the expression of three major type I classic cadherins E-, N-, and P-cadherin and their undercoat proteins alpha-, beta-, and gamma-catenin, and pp120 was investigated in 127 pituitary adenomas and 10 normal adenohypophyseal glands using an immunohistochemical technique with highly specific monoclonal antibodies. In normal pituitary glands, E-cadherin, catenins, and pp120 were strongly expressed on almost all hormone-producing cell-cell boundaries, N-cadherin was weakly immunoreactive on a few cell-cell boundaries, and P-cadherin was negative. In pituitary adenomas, a correlation was not identified among expression of E-cadherin, catenins, or pp120 with patient age, sex, hormone level, tumor size, and/or invasiveness, respectively. Expression of E-cadherin, catenins, and pp120 was significantly reduced in 24 growth hormone (GH) cell adenomas with prominent fibrous bodies compared with the other subtypes of pituitary adenomas and normal pituitary glands (p < 0.0001, respectively). Methylation-specific polymerase chain reaction analysis revealed that the E-cadherin gene promoter region was methylated in 6 of 16 (37.5%) GH cell adenomas with prominent fibrous bodies examined, 2 of which displayed total methylation, but not in 10 GH cell adenomas without fibrous bodies. No mutation of exon 3 of the beta-catenin gene was found in 16 GH cell adenomas with prominent fibrous bodies or in 10 other subtypes of pituitary adenomas that showed unremarkable intracellular presence of beta-catenin protein. In conclusion, the decreased expression of the E-cadherin catenin complex and methylation of the E-cadherin gene promoter region only in GH cell adenomas with prominent fibrous bodies may be an event associated with the formation of fibrous bodies.Endocrine Pathology 02/2002; 13(4):341-51. DOI:10.1385/EP:13:4:341 · 1.76 Impact Factor
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ABSTRACT: The majority of pituitary adenomas are trophically stable and change relatively little in size over many years. A comparatively small proportion behave more aggressively and come to clinical attention through inappropriate hormone secretion or adverse effects on surrounding structures. True malignant behaviour with metastatic spread is very atypical. Pituitary adenomas that come to surgery are predominantly monoclonal in origin and roughly half are aneuploid, indicating either ongoing genetic instability or transition through a period of genetic instability at some time during their development. Few are associated with the classical mechanisms of tumour formation but it is generally believed that the majority harbour quantitative if not qualitative differences in molecular composition compared to the normal pituitary. Despite their prevalence and the ready availability of biopsy material, at the present time, the precise molecular pathogenesis of the majority of pituitary adenomas remains unclear. This review summarizes current thinking.Frontiers in Neuroendocrinology 05/2003; 24(2):94-127. DOI:10.1016/S0091-3022(03)00012-8 · 7.04 Impact Factor
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ABSTRACT: Dysregulation of the Wnt signalling pathway contributes to developmental abnormalities and carcinogenesis of solid tumours. Here, we examined beta-catenin and adenomatous polyposis coli (APC) by mutational analysis in pituitary adenomas (n=60) and a large series of craniopharyngiomas (n=41). Furthermore, the expression pattern of beta-catenin was immunohistochemically analysed in a cohort of tumours and cysts of the sellar region including pituitary adenomas (n=58), craniopharyngiomas (n=57), arachnoidal cysts (n=8), Rathke's cleft cysts (n=10) and xanthogranulomas (n=6). Whereas APC mutations were not detectable in any tumour entity, beta-catenin mutations were present in 77% of craniopharyngiomas, exclusively of the adamantinomatous subtype. All mutations affected exon 3, which encodes the degradation targeting box of beta-catenin compatible with an accumulation of nuclear beta-catenin protein. In addition, a novel 81-bp deletion of this exonic region was detected in one case. Immunohistochemical analysis confirmed a shift from membrane-bound to nuclear accumulation of beta-catenin in 94% of the adamantinomatous tumours. Aberrant distribution patterns of beta-catenin were never observed in the other tumour entities under study. We conclude that beta-catenin mutations and/or nuclear accumulation serve as diagnostic hallmarks of the adamantinomatous variant, setting it apart from the papillary variant of craniopharyngioma.Acta Neuropathologica 07/2005; 109(6):589-97. DOI:10.1007/s00401-005-1004-x · 10.76 Impact Factor