Artikel
Mutational analysis of TOK-1 in pituitary adenomas
Mutationsanalyse von TOK-1 in Hypophysenadenomen
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Autoren
Veröffentlicht: | 4. Mai 2005 |
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Gliederung
Text
Objective
The gene encoding TOK-1 (BCCIP), a p21 binding protein and novel type of CDK2 modulator, is localized to chromosome 10q26. Recent studies suggest that a specific splice form, TOK-1a (BCCIPa), is an important cofactor for BRCA2 in tumor suppression. Due to frequent allelic deletions on chromosome 10q26 in pituitary tumors, a mutational analysis of TOK-1 in a large series of pituitary adenomas was performed.
Methods
Within the last decade, shock-frozen tumor samples from more than 500 patients with pituitary adenomas were collected. For RNA-/ and DNA extraction, the new Biorobot EZ1 automat (Qiagen) was used. In a series of 80 patients and 50 control samples, we studied the coding region of the TOK-1 gene using single-stranded-conformation-polymorphism (SSCP) analysis.
Results
We detected a point mutation in Exon 5 of the TOK-1 gene in one patient with an inactive pituitary adenoma causing a consecutive amino acid exchange from valin (GTG) to alanin (GCG). Furthermore, we detected a single nucleotide polymorphism from c>t just five bp in front of the Exon 7 starting site. This replacement was present in 2 tumors, but not in the control blood sample. Because Exon 7 is alternatively spliced resulting in two isoforms, TOK-1a and TOK-1b, further experiments will have to elucidate, whether the nucleotide exchange affects the splicing machinery.
Conclusions
This is the first study supporting a possible role of the CDK2/p21 modulator TOK-1 in the molecular pathogenesis of pituitary adenomas. Further analysis of the different splicing isoforms of TOK-1, their relevance with regard to the tumorigenesis and expression analysis utilizing a broader spectrum of tumor variants is mandatory to elucidate the role of TOK-1 in the development of neoplasms of the sellar region.