Genetic Testing for Hereditary MTC

Germiine defects in the RET protooncogene are responsible for MEN 2A, MEN 2B, and FMTC.41"43 RET encodes a transmembrane growth neurotrophic receptor with tyrosine kinase activity. In MEN 2A and FMTC, gain-of-function mutations within codons specifying cysteine residues in the extracellular ligand-binding domain of the RET gene product are most commonly found (see Table 15-2). In MEN 2B, a mutation is found in the intracellular tyrosine kinase domain. Changes in protein structure and function that result from these mutations predispose to neoplasia by a dominant oncogenic mechanism.44 Loss-of-function mutations in different regions of the same gene have been found in patients with Hirschsprung's disease. A small percentage of patients with MEN 2A have Hirschsprung's disease.8"10 All patients with MEN 2B have megacolon and constipation.4'10,11

Discovery of the genetic alterations underlying hereditary forms of MTC has allowed detection of disease gene carriers before calcitonin levels become elevated. Reliance upon a calcitonin test for clinical screening of kindred members at risk for MTC has certain drawbacks. First, a positive basal or stimulated calcitonin test indicates that cancer has probably already developed. A few of these patients develop distant metastatic disease, even after thyroidectomy with removal of tiny (1-mm) primary tumors. These patients would benefit from earlier thyroidectomy. Second, because the disease is inherited in an autosomal dominant fashion, 50% of at-risk patients never develop disease and are spared the expense and inconvenience of routine scheduled testing if a definitive genetic test is applied. Third, the provocative calcitonin test is unpleasant and uncomfortable, and some patients do not keep scheduled testing appointments because of this. In principle, genetic testing, which requires the drawing of blood for extraction of lymphocyte DNA, needs to be performed only once in an at-risk individual's lifetime. Stimulated calcitonin testing remains an important modality in monitoring patients for recurrent or residual disease after thyroidectomy.

To test a patient for the presence of a mutation in RET, peripheral blood is drawn and the lymphocyte pellet is separated. Lymphocytes have nuclei, as opposed to red blood cells, and DNA is extracted by proteinase digestion and phenol extraction. Regions of the RET protooncogene are amplified by polymerase chain reaction, and mutations are detected by one of several techniques. These include direct DNA sequencing, analysis of restriction sites introduced or deleted by a mutation, and gel shift analysis (denaturing gradient gel electrophoresis or single-strand conformation polymorphism analysis).

Constipation Prescription

Constipation Prescription

Did you ever think feeling angry and irritable could be a symptom of constipation? A horrible fullness and pressing sharp pains against the bladders can’t help but affect your mood. Sometimes you just want everyone to leave you alone and sleep to escape the pain. It is virtually impossible to be constipated and keep a sunny disposition. Follow the steps in this guide to alleviate constipation and lead a happier healthy life.

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