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[Molecular diagnosis of multiple type 2 endocrine neoplasia]
Abstract:
The paper reviews the data on the molecular structure of the protooncogene RET encoding for receptor-type protein kinase, on the mechanism of transformation of the normal protooncogene RET to a dominant transforming oncogene, and on RET mutations detected in patients with the MEN-2 syndrome. Moreover, it presents the authors' own findings. The familial medullary thyroid carcinoma burdened genealogy shows a new point mutation TCG(Ser)-->GCG(Ala) in codon 891, in the exon 15 of the protooncogene RET. This mutation was not detected in the chromosomes of healthy individuals. Analyzing the linkage with two known and two new polymorphic markers showed that there was a cisaggregation of informative polymorphic markers, phenotypic manifestation of the disease, and mutations in the genealogy in question. In the protooncogene RET, there were two new polymorphisms: G/A at position 24 in intron 14 and C/T in codon 836 (exon 14). The rate of the polymorphism encountered in codon 836 proved to be similar for the Russians and the Germans (0.96%), which was also seen for two earlier described polymorphisms in codon 691 (0.80 and 0.81, respectively) and in codon 904 (0.21 and 0.22). At the same time, there were statistically significant differences in the rates of intron 14 polymorphism (0.87 and 0.77, respectively). In a family having MEN 2, a proband displayed TGC-->CGC mutation in codon 634 of the gene RET in the heterozygous state. The mutation results in substitution of cysteine amino acid residue in the cysteine-rich extracellular domain of protein kinase encoded by the gene RET for arginine. The results of molecular analysis were used to confirm its clinical diagnosis and to indicate that effective care should be delivered in MEN 2a.
Insights
Researchers identified a new RET proto-oncogene mutation in a familial medullary thyroid carcinoma linked to Multiple Endocrine Neoplasia type 2 (MEN 2). This discovery aids in diagnosing and managing MEN 2a.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The proto-oncogene RET encodes a receptor-type protein kinase implicated in cancer development.
- Multiple Endocrine Neoplasia type 2 (MEN 2) syndromes are associated with RET gene mutations.
- Understanding RET proto-oncogene alterations is crucial for diagnosing and managing MEN 2.
Purpose of the Study:
- To review existing data on the RET proto-oncogene, its transformation mechanisms, and known mutations in MEN 2.
- To present novel findings on RET proto-oncogene mutations and polymorphisms in familial medullary thyroid carcinoma and MEN 2 patients.
- To investigate the correlation between genetic markers, disease phenotype, and RET mutations in affected families.
Main Methods:
- Review of existing literature on the RET proto-oncogene.
- Identification and characterization of point mutations and polymorphisms in the RET gene.
- Analysis of linkage between polymorphic markers, disease manifestation, and mutations in genealogies.
- Molecular analysis of RET gene mutations in patients with MEN 2.
Main Results:
- A novel point mutation (TCG(Ser)-->GCG(Ala)) in codon 891 of the RET proto-oncogene was identified in a familial medullary thyroid carcinoma, absent in healthy individuals.
- Two new polymorphisms were discovered: G/A at position 24 in intron 14 and C/T in codon 836 (exon 14) of the RET proto-oncogene.
- Statistically significant differences in intron 14 polymorphism rates were observed between Russian and German populations.
- A TGC-->CGC mutation in codon 634 of the RET gene was found in a MEN 2a proband, confirming clinical diagnosis.
Conclusions:
- The identified RET proto-oncogene mutation is linked to familial medullary thyroid carcinoma and MEN 2.
- New RET gene polymorphisms provide valuable markers for genetic studies and population comparisons.
- Molecular analysis of RET gene mutations is essential for accurate diagnosis and effective management of MEN 2a.
