Materiały źródłowe

• #1 Multiple Endocrine Neoplasias Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519054/

  Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary cancer syndrome associated primarily with tumors of the adrenal gland, thyroid and parathyroid. […] The germline RET mutations in MEN2 result in a gain of function of this tyrosine kinase receptor. This is different from many other inherited predispositions to neoplasia that are due to heritable „loss-of-function” mutations that inactivate tumor suppressor proteins. […] The number of different mutations causes MEN2A. The majority of the mutations in MEN2A variants occur in the cysteine-rich region of RET protein’s extracellular domain (coded by the genes in exon10 and 11), while mutations in the intracellular TK2 domain cause MEN2B-associated tumors. […] A single 918 Met to Thr mutation (M918T) in exon 16 is responsible for over 95% of cases of MEN2B.

• #2 Multiple Endocrine Neoplasia Type 2 (MEN2): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/123447-overview

  Multiple endocrine neoplasias type 2 (MEN2) is an inherited disorder characterized by the development of medullary thyroid cancer (MTC), parathyroid tumors, and pheochromocytoma. MEN2 results from germline mutations in the RET proto-oncogene and is transmitted in an autosomal dominant fashion. […] Mutations in RET, a transmembrane proto-oncogene, have been localized to 10q11.2 and are responsible for MEN 2. Although its function is still unknown, the protein produced by RET is critical during embryonic development of the enteric nervous system and kidneys. RET consists of 3 domains, including a cysteine-rich extracellular receptor domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain. […] Point mutations associated with MEN2A and the FMTC-only subtype have been identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists. Classical MEN2A is associated with germline missense mutations in RET codons 609, 611, 618, or 620 of exon 10 or codon 634 of exon 11, which map to the receptors extracellular cysteine-rich domain. MEN2A with cutaneous lichen amyloidosis is nearly always associated with mutation of codon 634, while patients with MEN2A and Hirschsprung disease typically harbor mutations involving RET exon 10.

• #3 Multiple Endocrine Neoplasia (MEN): Types & Symptoms

  https://my.clevelandclinic.org/health/diseases/23088-multiple-endocrine-neoplasia-men

  Multiple endocrine neoplasia type 2 (MEN2) is a genetic polyglandular (multiple glands) cancer syndrome. People with MEN2 will develop medullary thyroid cancer (carcinoma) and have an increased risk of developing other tumors that affect other glands in the endocrine system. […] MEN type 2 is caused by mutations of the RET gene, which is a gene that plays a role in the development of cancer. When working as it should, the RET gene helps control cell division and regulation of cell death. Mutations of the RET gene lead to uncontrolled growth of cells, causing tumors to form in certain organs and glands.

• #4 Multiple Endocrine Neoplasia Type 2 (MEN2): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/123447-overview

  Multiple endocrine neoplasias type 2 (MEN2) is an inherited disorder characterized by the development of medullary thyroid cancer (MTC), parathyroid tumors, and pheochromocytoma. MEN2 results from germline mutations in the RET proto-oncogene and is transmitted in an autosomal dominant fashion. […] Mutations in RET, a transmembrane proto-oncogene, have been localized to 10q11.2 and are responsible for MEN 2. Although its function is still unknown, the protein produced by RET is critical during embryonic development of the enteric nervous system and kidneys. RET consists of 3 domains, including a cysteine-rich extracellular receptor domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain. […] Point mutations associated with MEN2A and the FMTC-only subtype have been identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists. Classical MEN2A is associated with germline missense mutations in RET codons 609, 611, 618, or 620 of exon 10 or codon 634 of exon 11, which map to the receptors extracellular cysteine-rich domain. MEN2A with cutaneous lichen amyloidosis is nearly always associated with mutation of codon 634, while patients with MEN2A and Hirschsprung disease typically harbor mutations involving RET exon 10.

• #5 Multiple endocrine neoplasia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/multiple-endocrine-neoplasia/

  Mutations in the RET gene cause multiple endocrine neoplasia type 2. This gene provides instructions for producing a protein that is involved in signaling within cells. The RET protein triggers chemical reactions that instruct cells to respond to their environment, for example by dividing or maturing. Mutations in the RET gene overactivate the protein’s signaling function, which can trigger cell growth and division in the absence of signals from outside the cell. This unchecked cell division can lead to the formation of tumors in endocrine glands and other tissues. […] Mutations in the CDKN1B gene cause multiple endocrine neoplasia type 4. This gene provides instructions for making a protein called p27. Like the menin protein, p27 is a tumor suppressor that helps control the growth and division of cells. Mutations in the CDKN1B gene reduce the amount of functional p27, which allows cells to grow and divide unchecked. This unregulated cell division can lead to the development of tumors in endocrine glands and other tissues.

• #6 Multiple Endocrine Neoplasias Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519054/

  Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary cancer syndrome associated primarily with tumors of the adrenal gland, thyroid and parathyroid. […] The germline RET mutations in MEN2 result in a gain of function of this tyrosine kinase receptor. This is different from many other inherited predispositions to neoplasia that are due to heritable „loss-of-function” mutations that inactivate tumor suppressor proteins. […] The number of different mutations causes MEN2A. The majority of the mutations in MEN2A variants occur in the cysteine-rich region of RET protein’s extracellular domain (coded by the genes in exon10 and 11), while mutations in the intracellular TK2 domain cause MEN2B-associated tumors. […] A single 918 Met to Thr mutation (M918T) in exon 16 is responsible for over 95% of cases of MEN2B.

• #7 Multiple endocrine neoplasia type 2: An overview | Genetics in Medicine

  https://www.nature.com/articles/gim2011127

  Multiple endocrine neoplasia type 2 is historically composed of three clinical subtypes, all of which are associated with germline mutations in the RET proto-oncogene. […] The identification and phenotypic characterization of germline high-penetrance gain-of-function mutations in the RET proto-oncogene, encoding a receptor tyrosine kinase, as causing the great majority of multiple endocrine neoplasia (MEN) type 2 (MEN 2) heralded the era of accurate, evidence-based molecular diagnosis, predictive testing, genetic counseling, gene-informed cancer risk assessment, and preventative medicine. […] Gain-of-function mutations that produce a constitutively active protein or decreased specificity for its substrate cause MEN 2. […] Mutations in codons in the cysteine-rich extracellular domain (609, 611, 618, 620, and 634) cause ligand-independent RET dimerization, leading to constitutive activation (i.e., gain of function) of tyrosine kinase.

• #8 Multiple Endocrine Neoplasia Type 2 – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1257/

  Molecular pathogenesis of MEN2 involves the RET gene, which encodes a receptor tyrosine kinase. Pathogenic variants in RET lead to constitutive activation of the tyrosine kinase, resulting in the development of multiple endocrine neoplasia type 2 (MEN2). The most common pathogenic variants are non-conservative substitutions located in one of six cysteine codons in the extracellular domain of the encoded protein. These variants have been identified in families with MEN2A and some have been identified in families with familial medullary thyroid carcinoma (FMTC). Approximately 95% of all individuals with the MEN2B phenotype have a pathogenic variant in the tyrosine kinase domain of RET at codon 918 in exon 16, which substitutes a threonine for methionine. […] Gain of function is the mechanism of disease causation in MEN2. In MEN2A, the majority of pathogenic variants occur in the extracellular cysteine-rich domain, allowing for aberrant intermolecular disulfide bonds and resulting in ligand-independent RET kinase dimerization and subsequent constitutive activation of the RET kinase. In MEN2B, p.Met918Thr results in increased ATP binding and autophosphorylation and subsequent dimerization-independent activation of the RET kinase.

• #9 Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2 | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-molecular-mechanisms-ret-receptor-mediated-oncogenesis-S1807593222024000?covid=Dr56DrLjUdaMjzAgze452SzSInMN&rfr=truhgiz&y=kEzTXsahn8atJufRpNPuIGh67s1

  Evidence-based assessment of MEN 2 genotypic data demonstrate that not all RET mutations have equivalent clinical significance, although all reported mutations are thought to lead to ligand-independent constitutive activation of the RET receptor, autophosphorylation of RET, and aberrant stimulation of downstream signaling pathways. […] The most frequently identified RET mutations in MEN 2 affect cysteines in the extracellular cysteine-rich region; amino acid substitutions, resulting in replacement of a normal cysteine with any amino acid, lead to loss of intramolecular bonds and to an unpaired cysteine that is available for intermolecular interactions with other mutant RET proteins. […] Although the molecular mechanisms of activation are similar, cysteine RET mutations also vary in impact.

• #10 Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2 | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-molecular-mechanisms-ret-receptor-mediated-oncogenesis-S1807593222024000

  Multiple endocrine neoplasia type 2 is an inherited cancer syndrome characterized by tumors of thyroid and adrenal tissues. Germline mutations of the REarranged during Transfection (RET) proto-oncogene, leading to its unregulated activation, are the underlying cause of this disease. […] Current understanding of the molecular mechanisms of RET mutations and how they alter the structure and function of the RET protein leading to its aberrant activation, and the effects on RET localization and signaling are described. […] MEN 2 is dominantly inherited, and its genetic cause, mutations of the REarranged during Transfection (RET) proto-oncogene, was first recognized nearly 20 years ago. […] Evidence-based assessment of MEN 2 genotypic data demonstrate that not all RET mutations have equivalent clinical significance, although all reported mutations are thought to lead to ligand-independent constitutive activation of the RET receptor, autophosphorylation of RET, and aberrant stimulation of downstream signaling pathways.

• #11 Multiple Endocrine Neoplasias Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519054/

  Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary cancer syndrome associated primarily with tumors of the adrenal gland, thyroid and parathyroid. […] The germline RET mutations in MEN2 result in a gain of function of this tyrosine kinase receptor. This is different from many other inherited predispositions to neoplasia that are due to heritable „loss-of-function” mutations that inactivate tumor suppressor proteins. […] The number of different mutations causes MEN2A. The majority of the mutations in MEN2A variants occur in the cysteine-rich region of RET protein’s extracellular domain (coded by the genes in exon10 and 11), while mutations in the intracellular TK2 domain cause MEN2B-associated tumors. […] A single 918 Met to Thr mutation (M918T) in exon 16 is responsible for over 95% of cases of MEN2B.

• #12 Multiple endocrine neoplasia type 2: An overview | Genetics in Medicine

  https://www.nature.com/articles/gim2011127

  Multiple endocrine neoplasia type 2 is historically composed of three clinical subtypes, all of which are associated with germline mutations in the RET proto-oncogene. […] The identification and phenotypic characterization of germline high-penetrance gain-of-function mutations in the RET proto-oncogene, encoding a receptor tyrosine kinase, as causing the great majority of multiple endocrine neoplasia (MEN) type 2 (MEN 2) heralded the era of accurate, evidence-based molecular diagnosis, predictive testing, genetic counseling, gene-informed cancer risk assessment, and preventative medicine. […] Gain-of-function mutations that produce a constitutively active protein or decreased specificity for its substrate cause MEN 2. […] Mutations in codons in the cysteine-rich extracellular domain (609, 611, 618, 620, and 634) cause ligand-independent RET dimerization, leading to constitutive activation (i.e., gain of function) of tyrosine kinase.

• #13 Multiple Endocrine Neoplasia Type 2 – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1257/

  Molecular pathogenesis of MEN2 involves the RET gene, which encodes a receptor tyrosine kinase. Pathogenic variants in RET lead to constitutive activation of the tyrosine kinase, resulting in the development of multiple endocrine neoplasia type 2 (MEN2). The most common pathogenic variants are non-conservative substitutions located in one of six cysteine codons in the extracellular domain of the encoded protein. These variants have been identified in families with MEN2A and some have been identified in families with familial medullary thyroid carcinoma (FMTC). Approximately 95% of all individuals with the MEN2B phenotype have a pathogenic variant in the tyrosine kinase domain of RET at codon 918 in exon 16, which substitutes a threonine for methionine. […] Gain of function is the mechanism of disease causation in MEN2. In MEN2A, the majority of pathogenic variants occur in the extracellular cysteine-rich domain, allowing for aberrant intermolecular disulfide bonds and resulting in ligand-independent RET kinase dimerization and subsequent constitutive activation of the RET kinase. In MEN2B, p.Met918Thr results in increased ATP binding and autophosphorylation and subsequent dimerization-independent activation of the RET kinase.

• #14 Multiple Endocrine Neoplasias Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519054/

  Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary cancer syndrome associated primarily with tumors of the adrenal gland, thyroid and parathyroid. […] The germline RET mutations in MEN2 result in a gain of function of this tyrosine kinase receptor. This is different from many other inherited predispositions to neoplasia that are due to heritable „loss-of-function” mutations that inactivate tumor suppressor proteins. […] The number of different mutations causes MEN2A. The majority of the mutations in MEN2A variants occur in the cysteine-rich region of RET protein’s extracellular domain (coded by the genes in exon10 and 11), while mutations in the intracellular TK2 domain cause MEN2B-associated tumors. […] A single 918 Met to Thr mutation (M918T) in exon 16 is responsible for over 95% of cases of MEN2B.

• #15 Multiple endocrine neoplasia type 2: An overview | Genetics in Medicine

  https://www.nature.com/articles/gim2011127

  The disease-causing point mutation codon 918 that causes 95% of the MEN 2B phenotype lies within the substrate specificity pocket of the catalytic core of the tyrosine kinase and causes both a constitutive activation (i.e., gain of function) and perhaps loss of substrate specificity of the RET kinase in its monomeric state, independent of the normal ligand-binding and dimerization steps.

• #16 Multiple Endocrine Neoplasia Type 2 (MEN2): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/123447-overview

  Approximately 75% of MEN2B cases are sporadic and affected patients have de novo RET mutations, while 25% of cases occur in families with previous or current manifestations of MEN2B. Approximately 95% of patients with MEN2B have RET germline mutations in exon 16 (codon M918T) and fewer than 5% have RET germline mutations in exon 15 (codon A883F).

• #17 Multiple endocrine neoplasia syndromes – Symptoms, diagnosis and treatment | BMJ Best Practice

  https://bestpractice.bmj.com/topics/en-gb/866

  Multiple endocrine neoplasia syndromes are hereditary tumour syndromes with distinct patterns of organ involvement. […] Mutations in the RET proto-oncogene typically cause type 2 multiple endocrine neoplasia (MEN2). […] MEN2 is divided into subtypes, MEN2A and MEN2B (also known as MEN2 and MEN3). […] Prophylactic thyroidectomy in childhood is indicated in MEN2. […] Medical management of hormonal hypersecretion is important for symptom control. […] Most tumours require surgical evaluation, although surgical cure is not always possible. […] Genetic carriers require lifelong monitoring, even after successful operations. […] Morbidity and mortality result from both hormonal hypersecretion and metastases.

• #18 Multiple Endocrine Neoplasia Type 2 – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1257/

  Molecular pathogenesis of MEN2 involves the RET gene, which encodes a receptor tyrosine kinase. Pathogenic variants in RET lead to constitutive activation of the tyrosine kinase, resulting in the development of multiple endocrine neoplasia type 2 (MEN2). The most common pathogenic variants are non-conservative substitutions located in one of six cysteine codons in the extracellular domain of the encoded protein. These variants have been identified in families with MEN2A and some have been identified in families with familial medullary thyroid carcinoma (FMTC). Approximately 95% of all individuals with the MEN2B phenotype have a pathogenic variant in the tyrosine kinase domain of RET at codon 918 in exon 16, which substitutes a threonine for methionine. […] Gain of function is the mechanism of disease causation in MEN2. In MEN2A, the majority of pathogenic variants occur in the extracellular cysteine-rich domain, allowing for aberrant intermolecular disulfide bonds and resulting in ligand-independent RET kinase dimerization and subsequent constitutive activation of the RET kinase. In MEN2B, p.Met918Thr results in increased ATP binding and autophosphorylation and subsequent dimerization-independent activation of the RET kinase.

• #19 Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2 | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-molecular-mechanisms-ret-receptor-mediated-oncogenesis-S1807593222024000

  The most frequently identified RET mutations in MEN 2 affect cysteines in the extracellular cysteine-rich region (primarily residues between Cys515 and Cys634). […] Although the molecular mechanisms of activation are similar, cysteine RET mutations also vary in impact. […] The precise mechanisms by which these intracellular mutations activate RET are various, but it is suggested that they all do so through destabilizing the inactive form of RET, and shifting the equilibrium of RET receptors towards the active state. […] Over 95% of MEN 2B cases are associated with the same methionine to threonine change at codon 918 (M918T) in the RET kinase domain. […] The M918T mutation appears to increase the stability of monomeric active forms of RET, but activation of these mutants can also be further enhanced by binding of GDNF-GFR complexes, suggesting that these mutant RET forms may induce signal transduction from both within and outside the lipid rafts. […] The landscape of MEN 2 disease management has been transformed by the identification and cataloguing of its underlying genetic causes.

• #20 Multiple Endocrine Neoplasia Type 2 (MEN2): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/123447-overview

  Multiple endocrine neoplasias type 2 (MEN2) is an inherited disorder characterized by the development of medullary thyroid cancer (MTC), parathyroid tumors, and pheochromocytoma. MEN2 results from germline mutations in the RET proto-oncogene and is transmitted in an autosomal dominant fashion. […] Mutations in RET, a transmembrane proto-oncogene, have been localized to 10q11.2 and are responsible for MEN 2. Although its function is still unknown, the protein produced by RET is critical during embryonic development of the enteric nervous system and kidneys. RET consists of 3 domains, including a cysteine-rich extracellular receptor domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain. […] Point mutations associated with MEN2A and the FMTC-only subtype have been identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists. Classical MEN2A is associated with germline missense mutations in RET codons 609, 611, 618, or 620 of exon 10 or codon 634 of exon 11, which map to the receptors extracellular cysteine-rich domain. MEN2A with cutaneous lichen amyloidosis is nearly always associated with mutation of codon 634, while patients with MEN2A and Hirschsprung disease typically harbor mutations involving RET exon 10.

• #21 Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®) – NCI

  https://www.cancer.gov/publications/pdq/information-summaries/genetics/men2-hp-pdq

  Genotype-phenotype correlations in MEN2 are well established and have long been used to guide clinicians in making medical management recommendations. […] Several groups have developed pathogenic variant stratification tables based on clinical phenotype, age of onset, and aggressiveness of medullary thyroid cancer (MTC). […] ATA-Highest Risk (HST) RET pathogenic variants are the most aggressive and carry the highest risk of developing MTC. […] Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC. […] Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with multiple endocrine neoplasia type 2A (MEN2A). […] Moderate-risk variants located in exon 10 of the RET gene include variants in codons 609, 611, 618, 620, and 630. […] Research is ongoing into the role of neutral RET sequence variants in modifying the clinical presentation of patients with MEN2A.

• #22 Multiple Endocrine Neoplasia Type 2 (MEN2): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/123447-overview

  Approximately 75% of MEN2B cases are sporadic and affected patients have de novo RET mutations, while 25% of cases occur in families with previous or current manifestations of MEN2B. Approximately 95% of patients with MEN2B have RET germline mutations in exon 16 (codon M918T) and fewer than 5% have RET germline mutations in exon 15 (codon A883F).

• #23 Structure and function of RET in multiple endocrine neoplasia type 2 in: Endocrine-Related Cancer Volume 25 Issue 2 (2018)

  https://erc.bioscientifica.com/view/journals/erc/25/2/ERC-17-0354.xml

  Mutations affecting the intracellular domain of RET, usually associated with FMTC and always with MEN2B, signal independently of GDNF apparently as monomeric oncoproteins. […] These oncoproteins show not only an altered catalytic activity but also an altered substrate specificity because, contrary to wild-type (WT) RET, they tend to phosphorylate substrates that are usually preferred by cytoplasmic tyrosine kinases such as SRC and FAK. […] While activation loop Y905 is required for the transforming activity and signaling of RET-MEN2A mutations, the transforming activity of RET-MEN2B significantly decreased by replacing tyrosine 864 or 952 to phenylalanine being in this case independent of activation loop Y905. […] This short review will focus on the structural and molecular determinants for RET catalytic domain activity at the atomic and molecular levels as a ground to understand how oncogenic mutations found in MEN2 (many of them targeting the catalytic domain) corrupt these mechanisms.

• #24 Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2 | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-molecular-mechanisms-ret-receptor-mediated-oncogenesis-S1807593222024000?covid=Dr56DrLjUdaMjzAgze452SzSInMN&rfr=truhgiz&y=kEzTXsahn8atJufRpNPuIGh67s1

  In general, mutations located closer to the RET transmembrane domain have greater transforming ability and are linked to increased risks of more aggressive MEN 2 disease. […] The precise mechanisms by which these intracellular mutations activate RET are various, but it is suggested that they all do so through destabilizing the inactive form of RET, and shifting the equilibrium of RET receptors towards the active state. […] Over 95% of MEN 2B cases are associated with the same methionine to threonine change at codon 918 (M918T) in the RET kinase domain. […] The M918T mutation appears to increase the stability of monomeric active forms of RET, but activation of these mutants can also be further enhanced by binding of GDNF-GFR complexes, suggesting that these mutant RET forms may induce signal transduction from both within and outside the lipid rafts. […] The landscape of MEN 2 disease management has been transformed by the identification and cataloguing of its underlying genetic causes.

• #25 Multiple endocrine neoplasia syndromes – Symptoms, diagnosis and treatment | BMJ Best Practice

  https://bestpractice.bmj.com/topics/en-gb/866

  Multiple endocrine neoplasia syndromes are hereditary tumour syndromes with distinct patterns of organ involvement. […] Mutations in the RET proto-oncogene typically cause type 2 multiple endocrine neoplasia (MEN2). […] MEN2 is divided into subtypes, MEN2A and MEN2B (also known as MEN2 and MEN3). […] Prophylactic thyroidectomy in childhood is indicated in MEN2. […] Medical management of hormonal hypersecretion is important for symptom control. […] Most tumours require surgical evaluation, although surgical cure is not always possible. […] Genetic carriers require lifelong monitoring, even after successful operations. […] Morbidity and mortality result from both hormonal hypersecretion and metastases.

• #26 Structure and function of RET in multiple endocrine neoplasia type 2 in: Endocrine-Related Cancer Volume 25 Issue 2 (2018)

  https://erc.bioscientifica.com/view/journals/erc/25/2/ERC-17-0354.xml

  Mutations affecting the intracellular domain of RET, usually associated with FMTC and always with MEN2B, signal independently of GDNF apparently as monomeric oncoproteins. […] These oncoproteins show not only an altered catalytic activity but also an altered substrate specificity because, contrary to wild-type (WT) RET, they tend to phosphorylate substrates that are usually preferred by cytoplasmic tyrosine kinases such as SRC and FAK. […] While activation loop Y905 is required for the transforming activity and signaling of RET-MEN2A mutations, the transforming activity of RET-MEN2B significantly decreased by replacing tyrosine 864 or 952 to phenylalanine being in this case independent of activation loop Y905. […] This short review will focus on the structural and molecular determinants for RET catalytic domain activity at the atomic and molecular levels as a ground to understand how oncogenic mutations found in MEN2 (many of them targeting the catalytic domain) corrupt these mechanisms.

• #27 Multiple Endocrine Neoplasias Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519054/

  Primary hyperparathyroidism is present is 10% to 25% of patients with MEN 2A, while it is not associated with MEN 2B. […] The disease is usually bilateral and multicentric including its precursor neoplastic C-cell hyperplasia. The disease in MEN2B may be more aggressive than MEN2A. The aggressiveness of the disease in each syndrome depends upon the type of mutation.

• #28 Multiple Endocrine Neoplasia (MEN) – Free Sketchy Medical Lesson

  https://www.sketchy.com/medical-lessons/multiple-endocrine-neoplasia-men

  Multiple endocrine neoplasia (MEN) is an inherited disorder characterized by the development of tumors in multiple endocrine organs, often at a young age. MEN type 2A (MEN2A) and MEN type 2B (MEN2B) are forms of multiple endocrine neoplasia caused by gain-of-function mutations in the RET proto-oncogene on chromosome 10. The RET gene encodes a receptor tyrosine kinase that is pivotal in the development of several forms of tumors in MEN2A and MEN2B. Both are primarily associated with medullary thyroid cancer, a malignancy originating from the parafollicular C cells. Unlike sporadic forms, in MEN2A and MEN2B, this cancer is usually preceded by diffuse, bilateral C cell hyperplasia. […] MEN2A and MEN2B are both linked with pheochromocytomas, which manifest similarly to their sporadic counterparts. Parathyroid hyperplasia causing primary hyperparathyroidism is specific to MEN2A, while MEN2B is unique in presenting with mucosal neuromas on the tongue, lips, and buccal mucosa. MEN2B may also manifest GI abnormalities due to intestinal ganglioneuromatosis and can present with a Marfanoid habitus characterized by lordosis, kyphosis, and elongation of long bones.

• #29 Multiple Endocrine Neoplasias Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519054/

  Identification of these specific mutations is very important as it significantly impacts screening, diagnosis, and treatment, for example, the M918T mutation in exon 16 is considered a high-risk mutation for MEN2B cases and needs aggressive screening and prophylactic treatment to decrease morbidity and mortality. […] All of these conditions are due to one of the several RET proto-oncogene mutations which play an important role in the growth and differentiation of the structures mostly evolved from neural crest cells. […] Medullar thyroid cancer (MTC) is the most common manifestation of MEN2A and MEN2B with 100% penetrance and usually the first manifestation in MEN2 patients. […] Pheochromocytoma, a typically benign adrenal medullary tumor (usually bilateral and multicentric), occurs in 40% to 50% of patients with MEN2A or MEN2B; the frequency and penetration highly depend on the specific type of mutation.

• #30 Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®): Genetics – Health Professional Information [NCI] – Women’s Health – Associates for Women’s Medicine – Syracuse NY Gynecologist, Gynecology, Obstetrics, OBGYN, OB Physicians, Syracuse New York, Fayettevill

  https://www.afwomensmed.com/health-library/hw-view.php?DOCHWID=ncicdr0000813377

  MEN2 is caused by pathogenic variants in the RET gene. […] The understanding of MEN2’s natural history continues to evolve. […] Current stratification has moved away from a solely phenotype-based classification to one that is based on genotype (i.e., the pathogenic variant) and phenotype. […] The specific pathogenic variants and their ATA classification are summarized in Table 1 below. […] ATA-Highest Risk (HST) RET pathogenic variants are the most aggressive and carry the highest risk of developing MTC. […] Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC. […] Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with multiple endocrine neoplasia type 2A (MEN2A). […] Moderate-risk variants located in exon 10 of the RET gene include variants in codons 609, 611, 618, 620, and 630. […] Research is ongoing into the role of neutral RET sequence variants in modifying the clinical presentation of patients with MEN2A.

• #31 Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2 | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-molecular-mechanisms-ret-receptor-mediated-oncogenesis-S1807593222024000?covid=Dr56DrLjUdaMjzAgze452SzSInMN&rfr=truhgiz&y=kEzTXsahn8atJufRpNPuIGh67s1

  Evidence-based assessment of MEN 2 genotypic data demonstrate that not all RET mutations have equivalent clinical significance, although all reported mutations are thought to lead to ligand-independent constitutive activation of the RET receptor, autophosphorylation of RET, and aberrant stimulation of downstream signaling pathways. […] The most frequently identified RET mutations in MEN 2 affect cysteines in the extracellular cysteine-rich region; amino acid substitutions, resulting in replacement of a normal cysteine with any amino acid, lead to loss of intramolecular bonds and to an unpaired cysteine that is available for intermolecular interactions with other mutant RET proteins. […] Although the molecular mechanisms of activation are similar, cysteine RET mutations also vary in impact.

• #32 Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®) – NCI

  https://www.cancer.gov/publications/pdq/information-summaries/genetics/men2-hp-pdq

  Genotype-phenotype correlations in MEN2 are well established and have long been used to guide clinicians in making medical management recommendations. […] Several groups have developed pathogenic variant stratification tables based on clinical phenotype, age of onset, and aggressiveness of medullary thyroid cancer (MTC). […] ATA-Highest Risk (HST) RET pathogenic variants are the most aggressive and carry the highest risk of developing MTC. […] Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC. […] Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with multiple endocrine neoplasia type 2A (MEN2A). […] Moderate-risk variants located in exon 10 of the RET gene include variants in codons 609, 611, 618, 620, and 630. […] Research is ongoing into the role of neutral RET sequence variants in modifying the clinical presentation of patients with MEN2A.

• #33 Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®): Genetics – Health Professional Information [NCI] | Kaiser Permanente

  https://healthy.kaiserpermanente.org/health-wellness/health-encyclopedia/he.multiple-endocrine-neoplasia-type-2-men2-pdq%C2%AE-genetics-health-professional-information-nci.ncicdr0000813377

  The risk of inheriting the RET pathogenic variant is 50% in children of individuals with MEN2. […] The specific pathogenic variants and their ATA classification are summarized in Table 1 below. […] Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC. […] Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with multiple endocrine neoplasia type 2A (MEN2A). […] The risk of developing MTC by age 50 years ranged from 18% to 95%, depending on the codon, with codon 620 having the highest penetrance. […] The MEN2B RET variant M918T is associated with approximately 100% incidence of MTC in the first years of life and is considered the most aggressive MEN2 phenotype.

• #34 Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®): Genetics – Health Professional Information [NCI] – Women’s Health – Associates for Women’s Medicine – Syracuse NY Gynecologist, Gynecology, Obstetrics, OBGYN, OB Physicians, Syracuse New York, Fayettevill

  https://www.afwomensmed.com/health-library/hw-view.php?DOCHWID=ncicdr0000813377

  MEN2 is caused by pathogenic variants in the RET gene. […] The understanding of MEN2’s natural history continues to evolve. […] Current stratification has moved away from a solely phenotype-based classification to one that is based on genotype (i.e., the pathogenic variant) and phenotype. […] The specific pathogenic variants and their ATA classification are summarized in Table 1 below. […] ATA-Highest Risk (HST) RET pathogenic variants are the most aggressive and carry the highest risk of developing MTC. […] Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC. […] Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with multiple endocrine neoplasia type 2A (MEN2A). […] Moderate-risk variants located in exon 10 of the RET gene include variants in codons 609, 611, 618, 620, and 630. […] Research is ongoing into the role of neutral RET sequence variants in modifying the clinical presentation of patients with MEN2A.

• #35 Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®): Genetics – Health Professional Information [NCI] – Women’s Health – Associates for Women’s Medicine – Syracuse NY Gynecologist, Gynecology, Obstetrics, OBGYN, OB Physicians, Syracuse New York, Fayettevill

  https://www.afwomensmed.com/health-library/hw-view.php?DOCHWID=ncicdr0000813377

  MEN2 is caused by pathogenic variants in the RET gene. […] The understanding of MEN2’s natural history continues to evolve. […] Current stratification has moved away from a solely phenotype-based classification to one that is based on genotype (i.e., the pathogenic variant) and phenotype. […] The specific pathogenic variants and their ATA classification are summarized in Table 1 below. […] ATA-Highest Risk (HST) RET pathogenic variants are the most aggressive and carry the highest risk of developing MTC. […] Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC. […] Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with multiple endocrine neoplasia type 2A (MEN2A). […] Moderate-risk variants located in exon 10 of the RET gene include variants in codons 609, 611, 618, 620, and 630. […] Research is ongoing into the role of neutral RET sequence variants in modifying the clinical presentation of patients with MEN2A.

• #36 A Unique Presentation of Multiple Endocrine Neoplasia Type 2A | ACS

  https://www.facs.org/for-medical-professionals/news-publications/journals/case-reviews/issues/v4n8/20-romero-arenas-men2/

  Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder due to a genetic defect in the RET proto-oncogene, causing multicentric tumor formation in organs where the RET gene is expressed. […] Genetic testing confirmed a mutation at codon 634 of the RET proto-oncogene, the most common mutation for MEN2A. […] In the human genome, the most frequently-identified RET mutation responsible for MEN2A involves the substitution of cysteine at codon 634 on exon 11.1 While this mutation is well-established in MEN2A, this case report presents the first documented instance of megacolon associated with this specific mutation. […] This case expands the known spectrum of mutations potentially associated with the MEN2A-megacolon phenotype by identifying a mutation on exon 11 beyond the previously reported mutations on exon 10. […] This finding suggests a broader mutational landscape for this rare complication.

• #37 Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®): Genetics – Health Professional Information [NCI] – Women’s Health – Associates for Women’s Medicine – Syracuse NY Gynecologist, Gynecology, Obstetrics, OBGYN, OB Physicians, Syracuse New York, Fayettevill

  https://www.afwomensmed.com/health-library/hw-view.php?DOCHWID=ncicdr0000813377

  MEN2 is caused by pathogenic variants in the RET gene. […] The understanding of MEN2’s natural history continues to evolve. […] Current stratification has moved away from a solely phenotype-based classification to one that is based on genotype (i.e., the pathogenic variant) and phenotype. […] The specific pathogenic variants and their ATA classification are summarized in Table 1 below. […] ATA-Highest Risk (HST) RET pathogenic variants are the most aggressive and carry the highest risk of developing MTC. […] Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC. […] Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with multiple endocrine neoplasia type 2A (MEN2A). […] Moderate-risk variants located in exon 10 of the RET gene include variants in codons 609, 611, 618, 620, and 630. […] Research is ongoing into the role of neutral RET sequence variants in modifying the clinical presentation of patients with MEN2A.

• #38 Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®): Genetics – Health Professional Information [NCI] | Kaiser Permanente

  https://healthy.kaiserpermanente.org/health-wellness/health-encyclopedia/he.multiple-endocrine-neoplasia-type-2-men2-pdq%C2%AE-genetics-health-professional-information-nci.ncicdr0000813377

  The risk of inheriting the RET pathogenic variant is 50% in children of individuals with MEN2. […] The specific pathogenic variants and their ATA classification are summarized in Table 1 below. […] Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC. […] Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with multiple endocrine neoplasia type 2A (MEN2A). […] The risk of developing MTC by age 50 years ranged from 18% to 95%, depending on the codon, with codon 620 having the highest penetrance. […] The MEN2B RET variant M918T is associated with approximately 100% incidence of MTC in the first years of life and is considered the most aggressive MEN2 phenotype.

• #39 Multiple Endocrine Neoplasia: Ocular Features – EyeWiki

  https://eyewiki.org/Multiple_Endocrine_Neoplasia:_Ocular_Features

  A correlation exists between the specific RET mutation and the clinical phenotype of an affected patient with medullary thyroid carcinoma (MTC) in MEN2. Patients with MEN2B expressing M918T mutations of the RET gene often present with disease in infancy and have the most aggressive form of MTC. […] RET is expressed in multiple tissues which include: thyroid parafollicular cells (C cells), parathyroid glands, enteric ganglia, adrenal chromaffin cells and both peripheral- and central-neurons. This explains the variable neoplastic patterns in patients with MEN2.

• #40 Multiple Endocrine Neoplasias Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519054/

  Identification of these specific mutations is very important as it significantly impacts screening, diagnosis, and treatment, for example, the M918T mutation in exon 16 is considered a high-risk mutation for MEN2B cases and needs aggressive screening and prophylactic treatment to decrease morbidity and mortality. […] All of these conditions are due to one of the several RET proto-oncogene mutations which play an important role in the growth and differentiation of the structures mostly evolved from neural crest cells. […] Medullar thyroid cancer (MTC) is the most common manifestation of MEN2A and MEN2B with 100% penetrance and usually the first manifestation in MEN2 patients. […] Pheochromocytoma, a typically benign adrenal medullary tumor (usually bilateral and multicentric), occurs in 40% to 50% of patients with MEN2A or MEN2B; the frequency and penetration highly depend on the specific type of mutation.

• #41 Multiple Endocrine Neoplasias Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519054/

  Identification of these specific mutations is very important as it significantly impacts screening, diagnosis, and treatment, for example, the M918T mutation in exon 16 is considered a high-risk mutation for MEN2B cases and needs aggressive screening and prophylactic treatment to decrease morbidity and mortality. […] All of these conditions are due to one of the several RET proto-oncogene mutations which play an important role in the growth and differentiation of the structures mostly evolved from neural crest cells. […] Medullar thyroid cancer (MTC) is the most common manifestation of MEN2A and MEN2B with 100% penetrance and usually the first manifestation in MEN2 patients. […] Pheochromocytoma, a typically benign adrenal medullary tumor (usually bilateral and multicentric), occurs in 40% to 50% of patients with MEN2A or MEN2B; the frequency and penetration highly depend on the specific type of mutation.

• #42 Multiple Endocrine Neoplasias Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519054/

  Primary hyperparathyroidism is present is 10% to 25% of patients with MEN 2A, while it is not associated with MEN 2B. […] The disease is usually bilateral and multicentric including its precursor neoplastic C-cell hyperplasia. The disease in MEN2B may be more aggressive than MEN2A. The aggressiveness of the disease in each syndrome depends upon the type of mutation.

• #43 Multiple Endocrine Neoplasia (MEN) – Free Sketchy Medical Lesson

  https://www.sketchy.com/medical-lessons/multiple-endocrine-neoplasia-men

  Multiple endocrine neoplasia (MEN) is an inherited disorder characterized by the development of tumors in multiple endocrine organs, often at a young age. MEN type 2A (MEN2A) and MEN type 2B (MEN2B) are forms of multiple endocrine neoplasia caused by gain-of-function mutations in the RET proto-oncogene on chromosome 10. The RET gene encodes a receptor tyrosine kinase that is pivotal in the development of several forms of tumors in MEN2A and MEN2B. Both are primarily associated with medullary thyroid cancer, a malignancy originating from the parafollicular C cells. Unlike sporadic forms, in MEN2A and MEN2B, this cancer is usually preceded by diffuse, bilateral C cell hyperplasia. […] MEN2A and MEN2B are both linked with pheochromocytomas, which manifest similarly to their sporadic counterparts. Parathyroid hyperplasia causing primary hyperparathyroidism is specific to MEN2A, while MEN2B is unique in presenting with mucosal neuromas on the tongue, lips, and buccal mucosa. MEN2B may also manifest GI abnormalities due to intestinal ganglioneuromatosis and can present with a Marfanoid habitus characterized by lordosis, kyphosis, and elongation of long bones.

• #44 Multiple Endocrine Neoplasias Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519054/

  Identification of these specific mutations is very important as it significantly impacts screening, diagnosis, and treatment, for example, the M918T mutation in exon 16 is considered a high-risk mutation for MEN2B cases and needs aggressive screening and prophylactic treatment to decrease morbidity and mortality. […] All of these conditions are due to one of the several RET proto-oncogene mutations which play an important role in the growth and differentiation of the structures mostly evolved from neural crest cells. […] Medullar thyroid cancer (MTC) is the most common manifestation of MEN2A and MEN2B with 100% penetrance and usually the first manifestation in MEN2 patients. […] Pheochromocytoma, a typically benign adrenal medullary tumor (usually bilateral and multicentric), occurs in 40% to 50% of patients with MEN2A or MEN2B; the frequency and penetration highly depend on the specific type of mutation.

• #45 Multiple Endocrine Neoplasia (MEN) Type 2 | American Thyroid Association

  https://www.thyroid.org/multiple-endocrine-neoplasia-men-type-2/

  MEN2 is due to a change (mutation) in a gene called RET. […] This gene mutation can be found with a blood test for genetic testing. […] If you have changes in this gene, you [and your family members] are at a higher risk of getting MTC and other tumors. […] It is important for your doctor to know the exact change you have in the RET gene to know your risk for getting the diseases in MEN2. […] In MEN 2, PHEO is usually a benign tumor and not cancer.

• #46 Multiple Endocrine Neoplasias Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519054/

  Primary hyperparathyroidism is present is 10% to 25% of patients with MEN 2A, while it is not associated with MEN 2B. […] The disease is usually bilateral and multicentric including its precursor neoplastic C-cell hyperplasia. The disease in MEN2B may be more aggressive than MEN2A. The aggressiveness of the disease in each syndrome depends upon the type of mutation.

• #47 Multiple endocrine neoplasia syndromes – Symptoms, diagnosis and treatment | BMJ Best Practice

  https://bestpractice.bmj.com/topics/en-gb/866

• #48 Multiple Endocrine Neoplasia Type 2 (MEN2): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/123447-overview

  Multiple endocrine neoplasias type 2 (MEN2) is an inherited disorder characterized by the development of medullary thyroid cancer (MTC), parathyroid tumors, and pheochromocytoma. MEN2 results from germline mutations in the RET proto-oncogene and is transmitted in an autosomal dominant fashion. […] Mutations in RET, a transmembrane proto-oncogene, have been localized to 10q11.2 and are responsible for MEN 2. Although its function is still unknown, the protein produced by RET is critical during embryonic development of the enteric nervous system and kidneys. RET consists of 3 domains, including a cysteine-rich extracellular receptor domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain. […] Point mutations associated with MEN2A and the FMTC-only subtype have been identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists. Classical MEN2A is associated with germline missense mutations in RET codons 609, 611, 618, or 620 of exon 10 or codon 634 of exon 11, which map to the receptors extracellular cysteine-rich domain. MEN2A with cutaneous lichen amyloidosis is nearly always associated with mutation of codon 634, while patients with MEN2A and Hirschsprung disease typically harbor mutations involving RET exon 10.

• #49 Multiple endocrine neoplasia type 2 — Knowledge Hub

  https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/multiple-endocrine-neoplasia-type-2/

  Multiple endocrine neoplasia type 2 is an inherited genetic condition characterised by a predisposition to hyperparathyroidism, medullary thyroid carcinoma, phaeochromocytoma and skeletal anomalies. […] Multiple endocrine neoplasia type 2 (MEN2) can be subclassified into MEN2A and MEN2B. MEN2A is inherited in an autosomal dominant pattern, and is characterised by a predisposition to medullary thyroid carcinoma (MTC), phaeochromocytoma and hyperparathyroidism. MEN2B is also an autosomal dominant condition, and predisposes to MTC, phaeochromocytoma, aero-digestive ganglioneuromatosis and skeletal anomalies. […] Constitutional (germline) pathogenic gain-of-function variants in the RET proto-oncogene, located on chromosome 10, are the molecular driver of MEN2. […] Genomic testing is the principle diagnostic test for MEN2. The condition should be considered in any patient presenting with medullary thyroid carcinoma, unilateral or bilateral phaeochromocytoma or primary hyperparathyroidism at a young age (45 years), or a family history of any of the above. […] MEN2 is inherited in an autosomal dominant pattern. The child of an individual with MEN2 has a 50% chance of inheriting the pathogenic RET variant. […] Management of MTC, phaeochromocytoma or primary hyperparathyroidism in patients with MEN2 should be led by a specialist multidisciplinary team.

• #50 Multiple endocrine neoplasia type 2 — Knowledge Hub

  https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/multiple-endocrine-neoplasia-type-2/

  Multiple endocrine neoplasia type 2 is an inherited genetic condition characterised by a predisposition to hyperparathyroidism, medullary thyroid carcinoma, phaeochromocytoma and skeletal anomalies. […] Multiple endocrine neoplasia type 2 (MEN2) can be subclassified into MEN2A and MEN2B. MEN2A is inherited in an autosomal dominant pattern, and is characterised by a predisposition to medullary thyroid carcinoma (MTC), phaeochromocytoma and hyperparathyroidism. MEN2B is also an autosomal dominant condition, and predisposes to MTC, phaeochromocytoma, aero-digestive ganglioneuromatosis and skeletal anomalies. […] Constitutional (germline) pathogenic gain-of-function variants in the RET proto-oncogene, located on chromosome 10, are the molecular driver of MEN2. […] Genomic testing is the principle diagnostic test for MEN2. The condition should be considered in any patient presenting with medullary thyroid carcinoma, unilateral or bilateral phaeochromocytoma or primary hyperparathyroidism at a young age (45 years), or a family history of any of the above. […] MEN2 is inherited in an autosomal dominant pattern. The child of an individual with MEN2 has a 50% chance of inheriting the pathogenic RET variant. […] Management of MTC, phaeochromocytoma or primary hyperparathyroidism in patients with MEN2 should be led by a specialist multidisciplinary team.

• #51 MEN 2b (Multiple Endocrine Neoplasia 2b) Sippels Syndrome | Iowa Head and Neck Protocols

  https://medicine.uiowa.edu/iowaprotocols/men-2b-multiple-endocrine-neoplasia-2b-sippels-syndrome

  MEN IIB is caused by mutations in the RET proto-oncogene, generally in the TK1 domain. […] Classic clinical symptoms include Medullary thyroid cancer in infancy or childhood, pheochromocytoma, marfanoid habitus (Tall, thin, increased joint laxity), mucosal neuromas (tongue, eyelids, GI tract). […] Early recognition is key to preventing metastatic medullary thyroid cancer. […] Tyrosine kinase inhibitors: vandetanib or cabozantinib. […] Multiple mucosal neuromas are a dominant feature of MEN 2b. […] Multiple endocrine neoplasia type 2: A review.

• #52 Multiple endocrine neoplasia syndromes – Symptoms, diagnosis and treatment | BMJ Best Practice

  https://bestpractice.bmj.com/topics/en-gb/866

• #53 Multiple endocrine neoplasia, type 2 (MEN 2) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/men-2/symptoms-causes/syc-20540486

  Multiple endocrine neoplasia, type 2, also called MEN 2, is a rare condition. It causes tumors in the thyroid and parathyroid glands, adrenal glands, lips, mouth, eyes and digestive tract. Genetic testing can find the changed gene that causes MEN 2. Health care providers can treat the health issues that gene may cause. […] MEN 2 is an inherited disorder. This means people who have the changed gene can pass it on to their children. Each child has a 50% chance of getting the disorder. […] MEN 2 can cause the parathyroid glands to put too much calcium into the blood. This is known as primary hyperparathyroidism. The parathyroid glands are located in your neck. The extra calcium in the blood can cause many issues, including weak bones, called osteoporosis, kidney stones and having to urinate a lot. Medullary thyroid cancer shows up as a lump on the thyroid or neck. It can be hard to swallow when the tumor is large or other symptoms if the cancer spreads outside the neck. […] People with MEN 2 also can have a condition called pheochromocytoma. This condition causes noncancerous tumors on an adrenal gland. The adrenal glands are located at the top of the kidneys. These tumors can release hormones that cause high blood pressure, sweating and other symptoms.

• #54 Multiple endocrine neoplasia, type 2 (MEN 2) | Health Library | Memorial Health System

  https://www.mhsystem.org/health-library/con-20536124/

  Multiple endocrine neoplasia, type 2, also called MEN 2, is a rare condition. It causes tumors in the thyroid and parathyroid glands, adrenal glands, lips, mouth, eyes and digestive tract. […] MEN 2 is an inherited disorder. This means people who have the changed gene can pass it on to their children. Each child has a 50% chance of getting the disorder. […] MEN 2 is an inherited condition. This means someone who has a changed gene that can cause MEN 2 can pass that gene on to their children. […] Genetic testing is used to find out if someone has a changed gene that causes MEN 2. Children of someone who has this changed gene could inherit it and develop MEN 2. […] If someone in your family is diagnosed with MEN 2, your health care provider will likely recommend you and your family members have genetic testing. This is because MEN 2 can be treated or managed by removing the thyroid gland early in life.

• #55 Multiple endocrine neoplasia type 2 pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Multiple_endocrine_neoplasia_type_2_pathophysiology

  The progression to multiple endocrine neoplasia type 2 usually involves the genetic mutations. The pathogenesis of multiple endocrine neoplasia type 2 involves a mutation of the RET gene. […] The common feature among the three subtypes of multiple endocrine neoplasia type 2 is a high propensity to develop medullary thyroid carcinoma. […] Most cases of multiple endocrine neoplasia type 2 are inherited in an autosomal dominant pattern, which means affected people may have affected siblings and relatives in successive generations (such as parents and children). An affected person usually has one parent with the condition. Some cases, however, result from new mutations in the RET proto-oncogene. These cases occur in people with no history of the disorder in their family. […] Germline mutations are responsible for sporadic multiple endocrine neoplasia type 2, while mutations in the cysteine residues in the exons of the RET protein product are common in familial multiple endocrine neoplasia type 2.

• #56 Multiple endocrine neoplasia type 2 – Wikipedia

  https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_2

  The protein produced by the RET gene plays an important role in the TGF-beta (transforming growth factor beta) signaling system. Because the TGF-beta system operates in nervous tissues throughout the body, variations in the RET gene can have effects in nervous tissues throughout the body. MEN2 generally results from a gain-of-function variant of a RET gene. Other diseases, such as Hirschsprung disease, result from loss-of-function variants. […] When inherited, multiple endocrine neoplasia type 2 is transmitted in an autosomal dominant pattern, which means affected people have one affected parent, and possibly affected siblings and children. Some cases, however, result from spontaneous new mutations in the RET gene. These cases occur in people with no family history of the disorder. In MEN2B, for example, about half of all cases arise as spontaneous new mutations.

• #57 Multiple Endocrine Neoplasia Type 2: Causes and Symptoms

  https://www.massgeneral.org/children/multiple-endocrine-neoplasia-type-2

  MEN2 is the result of a mutation in the RET gene. […] These mutations can be inherited or occur at random as a new mutation. This is called a sporadic mutation. MEN2A is typically an inherited disease. In about half of children who have MEN2B, the condition is a consequence of a sporadic mutation.

• #58 Multiple Endocrine Neoplasia Type 2: Causes and Symptoms

  https://www.massgeneral.org/children/multiple-endocrine-neoplasia-type-2

  MEN2 is the result of a mutation in the RET gene. […] These mutations can be inherited or occur at random as a new mutation. This is called a sporadic mutation. MEN2A is typically an inherited disease. In about half of children who have MEN2B, the condition is a consequence of a sporadic mutation.

• #59 Multiple Endocrine Neoplasia Type 2 (MEN2): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/123447-overview

  Approximately 75% of MEN2B cases are sporadic and affected patients have de novo RET mutations, while 25% of cases occur in families with previous or current manifestations of MEN2B. Approximately 95% of patients with MEN2B have RET germline mutations in exon 16 (codon M918T) and fewer than 5% have RET germline mutations in exon 15 (codon A883F).

• #60 Multiple endocrine neoplasia type 2 – Wikipedia

  https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_2

  The protein produced by the RET gene plays an important role in the TGF-beta (transforming growth factor beta) signaling system. Because the TGF-beta system operates in nervous tissues throughout the body, variations in the RET gene can have effects in nervous tissues throughout the body. MEN2 generally results from a gain-of-function variant of a RET gene. Other diseases, such as Hirschsprung disease, result from loss-of-function variants. […] When inherited, multiple endocrine neoplasia type 2 is transmitted in an autosomal dominant pattern, which means affected people have one affected parent, and possibly affected siblings and children. Some cases, however, result from spontaneous new mutations in the RET gene. These cases occur in people with no family history of the disorder. In MEN2B, for example, about half of all cases arise as spontaneous new mutations.

• #61 Multiple Endocrine Neoplasia Type 2: Causes and Symptoms

  https://www.massgeneral.org/children/multiple-endocrine-neoplasia-type-2

  MEN2 is the result of a mutation in the RET gene. […] These mutations can be inherited or occur at random as a new mutation. This is called a sporadic mutation. MEN2A is typically an inherited disease. In about half of children who have MEN2B, the condition is a consequence of a sporadic mutation.

• #62

  https://link.springer.com/article/10.1007/s10689-004-7022-3

  Although the gene responsible for multiple endocrine neoplasia type 2 (MEN2) was discovered many years ago, the exact mechanisms of tumor development in patients affected with RET germline mutations remain unknown. […] Recent data suggest that an overrepresentation of mutant RET as a second hit event might trigger tumorigenesis. […] However, alterations in other genes might contribute to this overrepresentation of RET or impact on MEN 2-related tumor development through completely different mechanisms and pathways. […] The final goal of further elucidating the natural history and pathogenesis of MEN2-related tumors should be the chance to offer patients with RET germline mutations an optimal cancer prevention (e.g. codon specific recommendations for prophylactic thyroidectomy) and treatment program, especially for metastatic medullary thyroid carcinoma for which presently no effective therapy other than surgery exists.

• #63

  https://link.springer.com/article/10.1007/s10689-004-7022-3

  Although the gene responsible for multiple endocrine neoplasia type 2 (MEN2) was discovered many years ago, the exact mechanisms of tumor development in patients affected with RET germline mutations remain unknown. […] Recent data suggest that an overrepresentation of mutant RET as a second hit event might trigger tumorigenesis. […] However, alterations in other genes might contribute to this overrepresentation of RET or impact on MEN 2-related tumor development through completely different mechanisms and pathways. […] The final goal of further elucidating the natural history and pathogenesis of MEN2-related tumors should be the chance to offer patients with RET germline mutations an optimal cancer prevention (e.g. codon specific recommendations for prophylactic thyroidectomy) and treatment program, especially for metastatic medullary thyroid carcinoma for which presently no effective therapy other than surgery exists.

• #64

  https://www.omim.org/entry/171400

  Pearson et al. (1973) studied 21 members of a kindred with surgically confirmed multiple endocrine neoplasms. […] Hamilton et al. (1978) suggested that an increased urinary epinephrine fraction is a sensitive and reliable screening test for pheochromocytoma in MEN II, comparable to the calcitonin radioimmunoassay for medullary carcinoma of the thyroid. […] Chen et al. (2023) reported a 3-generation family with MEN2A. […] The proband was diagnosed with a left adrenal pheochromocytoma at age 31 years and bilateral multiple medullary thyroid carcinoma (MTC) with lymph node metastasis at age 41 years. […] Multiple endocrine neoplasia type 2A is caused by mutation in the RET gene. […] The most consistent molecular genetic abnormality that has been found in pheochromocytomas and medullary thyroid cancers, either sporadic or part of MEN2, is loss of heterozygosity (LOH) on 1p.

• #65 Multiple endocrine neoplasia syndromes – Symptoms, diagnosis and treatment | BMJ Best Practice

  https://bestpractice.bmj.com/topics/en-gb/866

• #66 Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®): Genetics – Health Professional Information [NCI] – Women’s Health – Associates for Women’s Medicine – Syracuse NY Gynecologist, Gynecology, Obstetrics, OBGYN, OB Physicians, Syracuse New York, Fayettevill

  https://www.afwomensmed.com/health-library/hw-view.php?DOCHWID=ncicdr0000813377

  MEN2 is caused by pathogenic variants in the RET gene. […] The understanding of MEN2’s natural history continues to evolve. […] Current stratification has moved away from a solely phenotype-based classification to one that is based on genotype (i.e., the pathogenic variant) and phenotype. […] The specific pathogenic variants and their ATA classification are summarized in Table 1 below. […] ATA-Highest Risk (HST) RET pathogenic variants are the most aggressive and carry the highest risk of developing MTC. […] Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC. […] Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with multiple endocrine neoplasia type 2A (MEN2A). […] Moderate-risk variants located in exon 10 of the RET gene include variants in codons 609, 611, 618, 620, and 630. […] Research is ongoing into the role of neutral RET sequence variants in modifying the clinical presentation of patients with MEN2A.

• #67 Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®) – NCI

  https://www.cancer.gov/publications/pdq/information-summaries/genetics/men2-hp-pdq

  Genotype-phenotype correlations in MEN2 are well established and have long been used to guide clinicians in making medical management recommendations. […] Several groups have developed pathogenic variant stratification tables based on clinical phenotype, age of onset, and aggressiveness of medullary thyroid cancer (MTC). […] ATA-Highest Risk (HST) RET pathogenic variants are the most aggressive and carry the highest risk of developing MTC. […] Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC. […] Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with multiple endocrine neoplasia type 2A (MEN2A). […] Moderate-risk variants located in exon 10 of the RET gene include variants in codons 609, 611, 618, 620, and 630. […] Research is ongoing into the role of neutral RET sequence variants in modifying the clinical presentation of patients with MEN2A.

• #68 Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2 | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-molecular-mechanisms-ret-receptor-mediated-oncogenesis-S1807593222024000?covid=Dr56DrLjUdaMjzAgze452SzSInMN&rfr=truhgiz&y=kEzTXsahn8atJufRpNPuIGh67s1

  In general, mutations located closer to the RET transmembrane domain have greater transforming ability and are linked to increased risks of more aggressive MEN 2 disease. […] The precise mechanisms by which these intracellular mutations activate RET are various, but it is suggested that they all do so through destabilizing the inactive form of RET, and shifting the equilibrium of RET receptors towards the active state. […] Over 95% of MEN 2B cases are associated with the same methionine to threonine change at codon 918 (M918T) in the RET kinase domain. […] The M918T mutation appears to increase the stability of monomeric active forms of RET, but activation of these mutants can also be further enhanced by binding of GDNF-GFR complexes, suggesting that these mutant RET forms may induce signal transduction from both within and outside the lipid rafts. […] The landscape of MEN 2 disease management has been transformed by the identification and cataloguing of its underlying genetic causes.

• #69 Structure and function of RET in multiple endocrine neoplasia type 2 in: Endocrine-Related Cancer Volume 25 Issue 2 (2018)

  https://erc.bioscientifica.com/view/journals/erc/25/2/ERC-17-0354.xml

  Intensive work over the last two and a half decades on RET genetics, signaling and cell biology have provided the current paradigm for the functional, biological and clinical correlations associated with distinct RET oncogenic variants. […] However, the structural and molecular bases for RET catalytic domain activation and oncogenic deregulation remained largely elusive. […] Recent crystallographic and biochemical studies have started to provide key insights into the molecular and atomic details revealing unexpected and private mechanisms of actions and molecular determinants not previously envisioned. […] This information is crucial as current compounds used in the clinic to treat RET-positive cancers are not RET specific and do not provide a significant survival response; hence, better therapeutic options are needed.

• #70

  https://link.springer.com/article/10.1007/s10689-004-7022-3

  Although the gene responsible for multiple endocrine neoplasia type 2 (MEN2) was discovered many years ago, the exact mechanisms of tumor development in patients affected with RET germline mutations remain unknown. […] Recent data suggest that an overrepresentation of mutant RET as a second hit event might trigger tumorigenesis. […] However, alterations in other genes might contribute to this overrepresentation of RET or impact on MEN 2-related tumor development through completely different mechanisms and pathways. […] The final goal of further elucidating the natural history and pathogenesis of MEN2-related tumors should be the chance to offer patients with RET germline mutations an optimal cancer prevention (e.g. codon specific recommendations for prophylactic thyroidectomy) and treatment program, especially for metastatic medullary thyroid carcinoma for which presently no effective therapy other than surgery exists.

• #71 Structure and function of RET in multiple endocrine neoplasia type 2 in: Endocrine-Related Cancer Volume 25 Issue 2 (2018)

  https://erc.bioscientifica.com/view/journals/erc/25/2/ERC-17-0354.xml

  Recent studies indicate that RET belongs to the group of RTKs whose catalytic activity is not regulated by activation loop phosphorylation. […] Autophosphorylation in trans appears in the case of RET to be more complex than a simple recognition of primary sequence motifs containing an accessible phospho-site. […] Remarkably, oncogenic RET mutations promote autophosphorylation by increasing catalytic activity and generating at the same time a better intermolecular substrate caused by a greater flexibility, lower stability and higher ATP affinity. […] It is evident that regions flanking the catalytic domain also play important roles in the allosteric control of RET catalytic activity. […] Uncovering the structural and molecular determinants for RET catalytic domain activation and oncogenic deregulation, together with an emphasis on focused drug-design and drug discovery projects, will be crucial for the development of more potent and specific RET kinase inhibitors.

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