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Oncogenes and tumor suppressor genes
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
S. Giordano, S. Corso, P. Conrotto
Several types of mutations have been identified that lead to constitutive activation of receptors, which transmit a growth signal in the absence of the ligand (Figure 8). In some cases these mutations can induce constitutive dimerization, as a consequence of ligand-independent dimerization. This has been shown, for example, in the case of the RET oncogene in multiple endocrine neoplasia type 2. In other cases, activation can be due to mutations located in the tyrosine kinase domain, responsible for a conformational change of the kinase domain toward an active conformation. This is the case, for example, for Kit and Met genes in gastro-intestinal stromal tumors and hereditary papillary renal carcinomas, respectively. Another mechanism for generating an oncoprotein receptor is loss of sequence coding for the extracellular portion and fusion with a sequence containing a dimerization motif; this happens in the case of the trk and ret genes in thyroid tumors.
Rare Mendelian cancer syndromes and other cancers
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Multiple endocrine neoplasia type 2 (MEN2) is due to mutations in the RET gene. The main features are medullary thyroid cancer (MTC) and phaeochromocytomas. Annual biochemical screening for phaeochromocytomas is by measurement of 24-hour urinary metanephrines. Due to the high risk of MTC, mutation carriers are advised to have a prophylactic thyroidectomy. There are three subtypes of MEN2, known as MEN2A, MEN2B and familial medullary thyroid cancer (FMTC). Individuals with MEN2B may also have mucosal neuromas of the lips and tongue, ganglioneuromatosis of the gastrointestinal tract, and a ‘Marfanoid’ body habitus. The MTC in MEN2B typically develops in early childhood so surgery should normally be done in the first year of life. In other cases, thyroidectomy should be performed before age 5 years, unless certain low-risk criteria are met. Before undertaking any surgery in an individual with MEN2, biochemical screening should be arranged to exclude a functioning phaeochromocytoma. As for MEN1, the inheritance of MEN2 is autosomal dominant (see Chapter 25).
Data and Picture Interpretation Stations Cases 1–42
Published in Joseph Manjaly, Peter Kullar, Alison Carter, Richard Fox, ENT OSCEs: A Guide to Passing the DO-HNS and MRCS (ENT) OSCE, 2019
Joseph Manjaly, Peter Kullar, Alison Carter, Richard Fox
Which wider group of disorders is this type associated with? Multiple endocrine neoplasia type 2 (MEN2)
An updated patent review of rearranged during transfection (RET) kinase inhibitors (2016–present)
Published in Expert Opinion on Therapeutic Patents, 2022
RET fusions occur in papillary thyroid carcinoma, Spitzoid tumors, and non-small cell lung cancer (NSCLC)[10]. Gain-of-function point mutations lead to the development of familial and sporadic thyroid cancers. Missense mutations are often linked with autosomal dominant multiple endocrine neoplasia type 2 (MEN2) syndrome, which increases the risk of medullary thyroid carcinoma (MTC)[11]. Mutations of a cysteine residue are reported in >95% of MEN2A neoplasms[12], which increases disulfide bond formation between the two RET monomers causing ligand-independent activation of the RET complex. Mutations in the RET kinase domain result in increased ATP binding and decreased autoinhibition[12]. Apart from fusion and RET point-mutations, elevated expression of RET can contribute to tumor development [12]. Increased release of GFLs from tumor cells can impact the tumor microenvironment that can lead to autocrine activation of RET and contribute to tumor growth and metastasis. Elevated GFLs and RET are reported in neuroblastoma, renal cell carcinoma, and head and neck cancers [13–15].
The Clinical Spectrum of Multiple Endocrine Neoplasia Type 2A with Cutaneous Lichen Amyloidosis in Ethnic Han Chinese
Published in Cancer Investigation, 2018
Xiao-Ping Qi, Jian-Qiang Zhao, Zhi-Lie Cao, Er Fu, Feng Li, Yi-Hua Zhao, Guang-Ping Wang, Peng-Fei Li, Wo-Long Ma, Jian Guo, Hong Jia
The RET (REarranged during Transfection) proto-oncogene (OMIM: 164761) is mapped on chromosome 10q11.2, which contains 21 exons and encodes a tyrosine kinase receptor. RET is expressed in a variety of neural crest derived cells, branchial arches, and urogenital system (1–4). Germline mutations of RET leads to multiple endocrine neoplasia type 2 (MEN 2) in an autosomal dominant pattern. The 2 distinct forms of MEN 2 are subtyped as MEN 2A (OMIM: 171400) and MEN 2B (OMIM: 162300) (4). MEN 2A accounts for 95% of MEN 2 cases and has 4 variants: (1) classical MEN 2A, which is characterized by medullary thyroid carcinoma (MTC) in >95% of cases, pheochromocytoma (PHEO) in ∼50% cases and primary hyperparathyroidism (HPT) in ∼25% cases; (2) MEN 2A associated with cutaneous lichen amyloidosis (CLA); (3) MEN 2A associated with Hirschsprung disease; (4) familial MTC (FMTC, OMIM: 155240) which is specified by families or individuals with RET germline mutations only present MTC, a minimum of 4 family members with MTC, but neither PHEO norHPT (4). MEN 2B accounts for <5% and presents a highly aggressive MTC, PHEO, ganglioneuromatosis, and mucosal neuroma since infancy (4). Interestingly, the presence of CLA was initially observed specifically in MEN 2A patients with codon 634-RET mutations, which locate in extracellular region of RET protein. The CLA appears in the scapular region of the upper back, corresponding to dermatomes T2–T6 (1,4–17). Exceptionally, there are 2 mutations in each intracellular tyrosine kinase domains: RET p.V804M mutation within exon 14 in an American female with MTC and CLA (18), and RET p.S891A mutation within exon 15 in a Chinese FMTC family with cutaneous biphasic amyloidosis binding OSMR variant p.G513D (19).
Diagnosis of multiple endocrine neoplasia type 2B and management of its ocular features
Published in Ophthalmic Genetics, 2018
Elke O. Kreps, Isabelle Van Herzeele, Bert L. Callewaert
Multiple endocrine neoplasia type 2 (MEN 2) includes three subtypes: MEN 2A, familial medullary thyroid carcinoma (FMTC), and MEN 2B. All entities show medullary thyroid carcinoma (MTC) with typical onset in young adulthood, middle age, or early childhood, respectively(1). They are caused by heterozygous germline gain-of-function mutations in the RET proto-oncogene. The 2b subtype represents about 5% of MEN cases and, like MEN 2A, also predisposes to pheochromocytoma (2). In addition, mucosal neuromas are frequent, whereas marfanoid habitus and ganglioneuromatosis of the gastrointestinal tract are less penetrant (1). The exact incidences of the ophthalmic manifestations in molecularly confirmed MEN 2B are unknown, but nearly all patients show the characteristic prominent corneal nerves (3). Prominent corneal nerves are however an aspecific finding and have been noted in MEN 2A, congenital ichthyosis, Refsum’s disease, and leprosy and also in several ocular pathological conditions such as herpetic keratitis, Fuchs’ endothelial dystrophy, posterior polymorphous dystrophy, and keratoconus (1). However, none of these conditions are associated with perilimbal neuromas or alacrima. Our case illustrates the importance of recognizing the ocular features of MEN 2B, in order not to delay the diagnosis, and provides a successful therapeutic approach. Carotid artery dissection was the presenting feature in this case. It remains elusive whether the vascular anomalies are related to MEN type 2B. We excluded known relevant causes of hereditary vasculopathies and risk factors such as systemic hypertension and hypercholesterolemia were absent. Other (yet unconfirmed) pathology may underlie the vascular complications in this case, but vascular anomalies could also be underreported in MEN 2B(4). Therefore, besides tumor surveillance and/or prophylactic surgery, imaging of the vascular tree may be warranted in MEN 2B.