Disease relevance of Multiple Endocrine Neoplasia Type 2b

• In MEN 2A, MEN 2B, and FMTC, direct detection of RET mutations can be used to identify disease allele carriers prior to the development of clinically evident neoplasms [1].
• Constitutional mutations of the RET proto-oncogene have been identified in multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC) families [2].
• A single RET mutation, resulting in the substitution M918T, has been identified in 94% of cases of MEN 2B (which consists of MTC, pheochromocytoma and developmental abnormalities) [3].
• Recently identified mutations affecting different domains of the RET proto-oncogene are associated with Multiple Endocrine Neoplasia type 2A (MEN 2A) and type 2B (MEN 2B), familial and sporadic Medullary Thyroid Carcinomas (MTC) and Hirschsprung disease (HSCR) [4].
• METHODS: Eleven chronic asthma patients (8 men/3 women) with moderate-to-severe airway obstruction (FEV1 48.4%), 9 stable asthma patients (6 males/3 females) with normal spirometry (FEV1 84.0%) and a positive methacholine test and 14 healthy subjects (8/6) were enrolled in the study [5].

High impact information on Multiple Endocrine Neoplasia Type 2b

• We now show that MEN 2B is also associated with mutation of the RET proto-oncogene [6].
• A mutation in codon 664, causing the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein, was found in all nine unrelated MEN 2B patients studied [6].
• Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome that comprises three clinical subtypes: MEN type 2A (MEN-2A), MEN type 2B (MEN-2B), and familial medullary thyroid carcinoma (FMTC) [7].
• A single point mutation in the catalytic core region of the receptor tyrosine kinase, RET, has been observed in germ-line DNA of MEN 2B patients [8].
• In multiple endocrine neoplasia 2B (MEN-2B) patients expressing RET(M918T), nuclear enrichment of STAT3 and elevated expression of CXCR4 was detected in metastatic thyroid C-cell carcinoma in the liver [9].

Chemical compound and disease context of Multiple Endocrine Neoplasia Type 2b

• Mutations in FMTC and MEN 2A exclusively affect cysteine residues in exon 10 and 11 of RET, whereas in MEN 2B codon 918 in exon 16 is involved [10].
• Multiple endocrine neoplasia type 2B (MEN 2B) is caused by the mutation of a conserved methionine to a threonine in the catalytic domain of the RET kinase [11].
• We have compared the biological and biochemical activity of the TK domains of the wild type and MEN 2B Ret in the context of the RET/PTC [12].
• Studies on the role of sex steroids in the feedback control of gonadotropin concentrations in men. III. Androgen resistance in primary gonadal failure [13].
• Intraoperative (123)I-MIBG scanning is of substantial benefit for children with MEN 2B undergoing surgery for recurrent MTC [14].

Biological context of Multiple Endocrine Neoplasia Type 2b

• Sequence analysis of germ-line DNA from MEN 2B patients revealed the existence of the same point mutation in the RET protooncogene in 34 unrelated individuals [15].
• The mechanism by which the MEN2B mutation converts Ret into a potent oncogene is poorly understood [16].
• RET harboring the mutations C634R (MEN 2A) or M918T (MEN 2B), in contrast to wild-type RET, activates a NF-kappaB-dependent reporter construct upon transient transfection in HeLa cells [17].
• These data demonstrate that the MEN 2B point mutation alters the substrate specificity of receptor tyrosine kinases and suggest that the enhanced oncogenesis associated with the MEN 2B mutation may be due in part to alterations in receptor regulation [11].
• However, in contrast to the activated WT form, expression of the MEN 2B mutated Ret-ptc 2 results in the tyrosine phosphorylation of a panel of proteins which interestingly interact with Crk and Nck [18].

Anatomical context of Multiple Endocrine Neoplasia Type 2b

• Here we took advantage of two rat pheochromocytoma-derived cell lines (PC12/MEN2A and PC12/MEN2B) to investigate whether Ret-induced nerve growth factor (NGF) unresponsiveness might involve impairment of ERK signaling [19].
• The gold standards for diagnosis are histochemical study of the rectal mucosa and molecular analysis of RET, which in familial cases detects MEN 2B at a preclinical stage so that early total prophylactic thyroidectomy can be performed [20].

Gene context of Multiple Endocrine Neoplasia Type 2b

• Multiple endocrine neoplasia (MEN IIB) with Cushing's syndrome due to medullary thyroid carcinoma producing corticotropin-releasing hormone [21].
• We conclude that the normal expression of a human Ret proto-oncogene with the MEN 2B mutation does not cause any features of MEN 2B in mice [22].
• A relevant clinical question is whether ablation of either GDNF or GFR alpha-1 could alter penetrance or severity of the MEN2B syndrome [23].
• Multiple endocrine neoplasia type 2B (MEN 2B) is a familial cancer syndrome, in which the cardinal feature is medullary thyroid carcinoma (MTC), a malignant tumor arising from the calcitonin producing thyroid C-cells [24].
• The RET point mutations associated with MEN2A, MEN2B, or FMTC, or the chromosomal breakpoints and translocations associated with PTC, typically activate the RET receptor tyrosine kinase (RTK) [25].

Analytical, diagnostic and therapeutic context of Multiple Endocrine Neoplasia Type 2b

• RESULTS: Fifteen patients (MEN 2A [10], MEN 2B [2], VHL [3]) underwent laparotomy for cortical-sparing adrenalectomy [26].
• Because the incidence of MCT in MEN-IIb is virtually 100%, a total thyroidectomy in high risk patients--even before clinical evidence of malignant tumours--may be the only hope of cure [27].
• Early diagnosis of MEN IIb, which could be made by recognition of the typical clinical appearance, is of special importance because of the poor prognosis of MTC [28].
• The boiling-water extract of the herb was administered to 12 healthy volunteers (9 men/3 women) at a dosage of 100 mg/kg the anthraquinone levels in plasma were determined with TLC, HPLC, and LC-MS [29].

References