The RET gene codes for a protein that is part of a family of tyrosine kinase receptors. Most cancer predisposition syndromes are casued by mutations of tumour supressor genes. RET is one of the few identified exceptions to this rule; it is a proto-oncogene, mutations thus converting it into an oncogene.
On clinical grounds multiple endocrine neoplasia type 2 can be divided into MEN2A and MEN2B. Familial medullary carcinoma of the thyroid is a separate clinical entity. All three conditions are now known to be allelic, being caused by mutations in the RET gene; all are inherited as autosomal dominant traits. MEN2A is the most common. It is important to realise that not all cases of medullary carcinoma of the thyroid represent an inherited tendency. In cases of apparently sporadic MTC an underlying germ-line mutation can be expected in approximately 25%.
Ref: Companion to specialist surgical practice - Endocrine Surgery.
Germline Vs somatic mutation
RET proto-oncogene 10 pericentromeric
trans-membrane tyrosine kinase
limited number of known mutations
genetic testing 95% successful
pentagastrin test outdated
MEN2A= MTC, Bil Phaeo, 25% 10 HPT
634 Most aggressive, 75% 10 HPT
metastatic disease sometimes by 2 years of age
MEN2B=MTC, Bil Phaeo, Marfanoid, submucosal neuromata with classic facies, GI ganglioneuromatosis
918 mutation. Metastatic sometimes at birth
FMTC= 3 generations no associated tumours. Shares some mutations with MEN2A. Not 634
Best example of genetic screening leading to definitive surgical prophylaxis Virtual 100% penetrance of lethal malignancy
Prophylactic thyroidectomy=cure
MEN2B:1 month. 634 2A 2 years. Others >5years
Secondary prophylaxis for phaeo
HPT incidental issue
