Introduction: The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. Methods: The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document. Results: The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. Conclusions: The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendati...

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Revised American thyroid association guidelines for the management of medullary thyroid carcinoma

Background: Inherited and sporadic medullary thyroid cancer (MTC) is an uncommon and challenging malignancy. The American Thyroid association (ATA) chose to create specific MTC Clinical Guidelines that would bring together and update the diverse MTC literature and combine it with evidence-based medicine and the knowledge and experience of a panel of expert clinicians. Methods: Relevant articles were identified using a systematic PubMed search and supplemented with additional published materials. Evidence-based recommendations were created and then categorized using criteria adapted from the United States Preventive Services Task Force, Agency for Healthcare Research and Quality. Results: Clinical topics addressed in this scholarly dialog included: initial diagnosis and therapy of preclinical disease (including RET oncogene testing and the timing of prophylactic thyroidectomy), initial diagnosis and therapy of clinically apparent disease (including preoperative testing and imaging, extent of surgery, and h...

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Medullary thyroid cancer: management guidelines of the American Thyroid Association.

Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.

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Hirschsprung disease, associated syndromes and genetics: a review

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007

BACKGROUND:

The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene resulting from the chromosome inversion inv(2)(p21;p23) recently was identified in nonsmall cell lung cancer (NSCLC). The authors of this study investigated the frequency, genetic and clinicopathologic profiles of EML4-ALK in Chinese patients with NSCLC.



METHODS:

EML4-ALK was investigated in 266 resected primary NSCLC, including adenocarcinomas (AD), lymphoepithelioma-like carcinomas, squamous cell carcinomas, mucoepidermoid carcinomas, and adenosquamous carcinomas, by reverse transcriptase-polymerase chain reaction and was verified by sequencing. EML4-ALK protein expression was studied by immunohistochemistry.



RESULTS:

Thirteen tumors (4.9%) had EML4-ALK comprising 4 fusion transcript variants with fusion of the variable segments from 5′ EML4 to 3′ ALK and with preservation of the ALK kinase domain. The most common variant consisted of 8 tumors with variant 3 that involved EML4 exon 6. The others included 2 tumors with variant 1 (exon 13), 2 tumors with variant 2 (exon 20), and 1 tumor with the novel variant 5 (exon 18). There were 11 ADs and 2 unusual carcinomas with mixed squamous and glandular components. Immunohistochemistry demonstrated diffuse ALK fusion proteins in the tumor cell cytoplasm. EML4-ALK was associated with nonsmokers (P = .009). Tumors with the fusion gene had the wild-type epidermal growth factor receptor (EGFR) (P = .001) and v-Ki-ras2/Kirsten rat sarcoma viral oncogene homolog (KRAS) genes. Patients who had EML4-ALK-positive AD had a younger median age (P = .018) compared with patients who did not have the fusion gene.



CONCLUSIONS:

The EML4-ALK fusion gene was present in various histologic types of NSCLC. It occurred in mutual exclusion to EGFR and KRAS mutations and was associated with nonsmokers. The authors concluded that EML4-ALK may be useful for predicting the potential response to ALK inhibitors as a therapeutic option for patients with lung cancer. Cancer 2009. © 2009 American Cancer Society.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.24181

The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(02)08218-1.pdf

Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprung's disease.

Association of RET protooncogene codon 45 polymorphism with Hirschsprung disease.

HSP90AB1: Helping the good and the bad

The activation of the RET signaling pathway during embryogenesis is a crucial prerequisite for a directional migration of enteric nervous system progenitor cells. Loss-of-function germline mutations of the RET proto-oncogene are reported in familial and sporadic cases of Hirschsprung disease (HSCR) with a variable frequency. Furthermore, variants of several RET polymorphisms are over- or under-represented in HSCR populations. Specifically, the c.135A RET variant has been previously shown to be strongly associated with the HSCR phenotype. We have reported an HSCR-phenotype modifying effect of the RET c.135G>A polymorphism due to a within-gene interaction in patients harboring RET germline mutations, yet the function of the c.135G>A variant is unknown. The basic RET promoter region was investigated by DNA sequencing approach in 80 HSCR patients. Identified polymorphisms were genotyped in the HSCR and in a control population and haplotypes were reconstructed. The dual-luciferase assay was used to evaluate the activity of different RET promoter haplotypes. We demonstrate that variants of two RET promoter polymorphisms -5G>A and -1C>A from the transcription start site are associated with HSCR. Furthermore, the -5G>A polymorphism is in strong linkage disequilibrium with the c.135G>A polymorphism. The promoter haplotype -5/-1AC associated with HSCR has a significantly lower activity in an in vitro dual-luciferase expression assay compared with those haplotypes identified in the majority of normal controls. These data suggest a role for RET haplotypes containing the -5A promoter variant in the etiology of HSCR.

Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR)

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant inherited tumor syndrome comprising medullary thyroid carcinoma (MTC) as an obligatory feature. MEN2 is divided into three subtypes in accordance to the remaining tissues involved. Familial medullary thyroid carcinoma (FMTC) is characterized by an isolated MTC occurrence, while MEN2A cases have an association of pheochromocytoma and primary hyperparathyroidism in approximately 50% and 15% to 30%, respectively. MEN2B has a similar disease phenotype with an earlier onset of MTC, and rarely hyperparathyroidism. In addition, MEN2B individuals have a marfanoid habitus, abnormal facies, mucosal neuromas, hyperplasia of the enteric nerve plexi, and in some cases delayed puberty. 1

The RET protooncogene on 10q11.2 has been recognized as the susceptibility locus for MEN2. This gene is involved in the development of neural crest cell lineages by coding for a membrane-bound receptor tyrosine kinase. Several functional ligands of RET have been demonstrated: the glial cell line-derived neurotrophic factor (GDNF), the neurturin (NRTN), the artemin (ARTN), and the persephin (PSPN). These ligands, in association with the corresponding members of the GDNF family receptor alpha (GFRα-1–4), bind to the extracellular RET receptor domain, inducing a homodimerization of RET molecules and a specific activation of the intracellular tyrosine kinase domain. 2–5

Germline missense mutations of RET protooncogene have been detected in each one of six cysteine codons within exon 10 (codons 609, 611, 618, and 620) and exon 11 (codons 630 and 634), in about 95% of MEN2A and in up to 85% of FMTC families. 1,6–8 The substitution of one of these highly conserved cysteine residues results in RET monomers capable of constitutive dimerization in the absence of functional RET ligands. 9,10 In addition to these common cysteine codon mutations, some rare noncysteine mutations located within the intracellular tyrosine kinase domain of RET have been described. 11,12 The effects of these mutations are unclear, but the E768D (exon 13) and V804L (exon 14) mutations also increase the transforming activity, possibly by altering the substrate specificity or the ATP-binding capacity of RET, thus modifying the kinase activity. 13

Because of the assumed complete penetrance of MTC in MEN2 families and the reliability of genetic analysis for MEN2-associated RET germline mutations, predictive testing has become a routine procedure in the management of MEN2 kindreds. Such tests allow the presymptomatic identification of individuals at risk, permitting prophylactic thyroidectomy before C-cell carcinoma occurs. 1,14,15 According to the reported de novo mutation rate of up to 9% in MEN2A/FMTC, and a sometimes unknown family history, the genetic analysis should be expanded on all patients with an apparently sporadic MTC to exclude a hereditary form of this tumor or to identify index cases of new MEN2 kindreds. 16

In this study we have investigated a population of apparently sporadic MTC patients and revealed RET germline mutations in codons 790 and 791 in four of five cases. We were particularly interested in the genotype–phenotype correlation in MEN2 kindreds with codons 790/791 germline mutations of RET protooncogene. Mutations of these two codons have been previously reported and were described as associated with incomplete penetrance in MEN2A/FMTC phenotype. 12 Similarly to these data, our identified at-risk subjects were biochemically analyzed, but we have additionally performed a prophylactic thyroidectomy due to the diverse penetrance pattern found in the present study.

Guido Fitze

Papers

Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprung's disease.

Association of RET protooncogene codon 45 polymorphism with Hirschsprung disease.

HSP90AB1: Helping the good and the bad

Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR)

Various penetrance of familial medullary thyroid carcinoma in patients with RET protooncogene codon 790/791 germline mutations.