Analysis of beta-catenin mutations and alpha-, beta-, and gamma-catenin expression in normal and neoplastic human pituitary tissues.
The cadherin-catenin system mediates Ca(2+)-dependent cell-cell adhesion, and genetic alterations in these molecules play a significant role in multistage carcinogenesis. Mutations in the beta-catenin gene, mostly affecting exon 3, have been detected in malignant cell lines and in primary tumors. Immunohistochemical abnormalities in alpha-, beta-, and gamma-catenin have been reported in malignant and benign tumors, and nuclear localization of beta-catenin has been associated with mutations in exon 3 of this gene. Mutational analysis of exon 3 of the beta-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 beta-catenin. We also analyzed immunohistochemical expression of alpha-, beta-, and gamma-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 beta-catenin and was used for PCR and sequencing of exon 3 of the beta-catenin gene. No mutations in exon 3 of the beta-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 beta-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 alpha-catenin were positive in fewer tumors than for beta-catenin. The lowest frequency immunopositive tumors and the weakest immunostaining was for gamma-catenin. All medically treated prolactinomas were negative for gamma-catenin, whereas treated growth hormone adenomas were less often positive for both alpha- and gamma-catenin than for untreated tumors. The percentage of positive cases for beta-catenin was the same in these two groups. Most pituitary carcinomas were negative for both alpha- and gamma-catenin but were beta-catenin positive. These results indicate that (i) mutations in exon 3 of the beta-catenin gene are uncommon in pituitary tumors, and (ii) expression of alpha-, beta-, and gamma-catenin is decreased in pituitary adenomas compared to normal pituitary tissues.
Tziortzioti
V
V
Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
Ruebel
K H
KH
Kuroki
T
T
Jin
L
L
Scheithauer
B W
BW
Lloyd
R V
RV
D000236:Adenoma / Q000737:chemistry / Q000235:genetics; D002467:Cell Nucleus / Q000737:chemistry; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000235:genetics*; D004252:DNA Mutational Analysis; D051180:Desmoplakins; D005091:Exons; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D010902:Pituitary Gland / Q000737:chemistry / Q000648:ultrastructure; D010911:Pituitary Neoplasms / Q000737:chemistry / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D016610:Tissue Embedding; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D051178:alpha Catenin; D051176:beta Catenin; D051185:gamma Catenin
C495273:CTNNA1 protein, human; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; C495292:JUP protein, human; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin; D051185:gamma Catenin