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(2020-21 BY2PA2) Molecular Pathology > RET and MEN2 > Flashcards

RET and MEN2 Flashcards

1
Q
A
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2
Q

Why Study RET (of all RTKs)?

A
  • Human diseases are associated with both gain and loss of function mutations.
  • RET provides insight into mechanisms in cancer and developmental biology.
  • Identifying the RET mutations allows us to begin appropriate treatment earlier
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3
Q

What does RET stand for?

A

rearranged during transformation

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4
Q

THE RET SYSTEM- Receptors

A
  • RET (rearranged during transformation):

Receptor Tyrosine Kinase

  • GFRα(1-4) (GDNF family receptor-a, 1-4):

Accessory receptors that increase the affinity of the ligands for RET.

Glycosylphosphatidylinositol-linked (NOT transmembrane)

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5
Q

Structure of RET

A
  • Draw RET—cysteine rich domain & cadherin domain.
  • There are 3 isoforms of RET generated by alternate mRNA splicing:
  • RET51, RET43, RET9. They have different length tails AFTER the kinase domain
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6
Q

RET LIGANDS

A

GDNF family of ligands (GFLs)

  • GDNF (glial cell-derived neurotrophic factor)
  • NRTRN (Neurturin)
  • PRSP (Persephin)
  • ARTN (Artemin)

Different GFLs prefer different GFRαs

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7
Q

Show RET and its Accessory Receptors

A
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8
Q

RET signal transduction

A
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9
Q

Germline Mutations in RET

A
  • 98% of the cases of inherited MEN2 (multiple endocrine neoplasia Type 2) are associated with mutations in RET.
  • MEN2 is rare (1:30,000)
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10
Q

MEN2 has 2 Main Subtypes:

A
  1. MEN2A (FMTC is now seen as a subset)
  2. MEN2B

(About 25% of MTC (medullary thyroid carcinoma) is inherited and 75% is sporadic; Mutations in RET account for 40-50% of the sporadic)

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11
Q

Characteristics of MEN2 Subtypes: MEN2A

A
  • Medullary thyroid cancer
  • Pheochromocytoma
  • Hyperparathyroidism
  • MEN2A with Hirshsprung’s disease MEN2A with cutaneous lichen
  • amyloidosis
  • FMTC
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12
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13
Q

Characteristics of MEN2 Subtypes: MEN2A

A
  • Medullary thyroid cancer
  • Pheochromocytoma
  • Marfanoid habitus
  • Intestinal neuromas
  • mucosal ganglioneuromas
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14
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15
Q

Survival Rates for MEN2a and MEN2b

A

10 year survival rate:

  • 75% of MEN2B patients with medullary thyroid carcinoma (MTC).
  • 97% of MEN2A patients with MTC.

MEN2B is more aggressive since it is usually diagnosed later (denovo germline mutations with no family history)

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16
Q

Medullary Thyroid Carcinoma (MTC)

A

MTC is multi-centric, bilateral, and characterised by whitish nodules

17
Q

Genotype to Phenotype

A

Figure 1. RET proto-oncogene is the cause of MEN2. (A) The proto-oncogene RET is composed of 21 exons located on chromosome

  • 10 (10q11.2) and encodes for a transmembrane receptor tyrosine kinase. (B) The RET protein is composed of 3 functional
  • domains,including an extracellular ligand-binding domain, a transmembrane domain, and a cytoplasmic tyrosine kinase domain.
  • The extracellular domain contains a signal peptide that is cleaved, 4 cadherin-like repeats, and a cysteine-rich region critical for
  • disulfide bond formation needed in dimerization. (C) The locations of known RET mutations are highlighted according to American
  • Thyroid Association risk classification (blue 5 rating A; green 5 rating B; orange 5 rating C; red 5 rating D).
  • (D) Mutations are grouped by the MEN (multiple endocrine neoplasia) subtype they cause.
18
Q

Location of Common and Rare Mutations in RET

A
19
Q

Cysteine Residues are Mutated in MEN2a

A
  • Point mutations in one of six cysteine codons in the extracellular domain of RET are responsible for FMTC and MEN2A
  • C634 is mutated in 90% of MEN2A (C634R in >50%) (Frank-Raue estimates only 54% of MEN2A—may depend on the design of the genetic test)
  • C634, C618, C620 each accounts for about 30% of FMTC
20
Q

The Mutated Cysteines are in the Extracellular Domain of RET

A
21
Q

Mechanism of the Cysteine Mutations

A
  • Substitutions of cysteines activate RET as a dominant transforming gene by causing ligand-independent dimerization.
  • The substitution of a cysteine with another amino acid disrupts its normal intramolecular disulphide bond and leaves the partner cysteine free to form an intermolecular bond between RET molecules.
22
Q
A
23
Q

Forming Disulphide Bonds

A
24
Q

Structure of RET C634R Homodimers

A

(Receptor is autophosphorylated in the absence of ligand; dimers are held together by intermolecular disulphide bonds)

25
Q

MEN2B

A
  • medullary thyroid carcinoma (MTC; 100% of patients)
  • pheochromocytoma (tumours of the adrenal medulla; 50% of patients)
  • ganglioneuromatosis (tumours of the ganglion nerve cells of the gastrointestinal tract and mucosa; 40% of patients)
26
Q

TRUE or FALSE: MEN2B is the most aggressive version of MEN2

A

TRUE

27
Q

Ganglioneuromatosis

A

Neuromas in the mucosa in MEN2B

28
Q

MEN2B Is Caused by An Activating Mutation in the Cytoplasmic Domain of RET

A
  • The point mutation M918T is found in 95% of the
  • patients with MEN2B
  • M918T is ligand-independent—the mutant signals in the absence of GDNF.
  • M918 is in the substrate recognition pocket of RET’s tyrosine kinase domain.
  • M918T results in increased kinase activity and an expanded range of substrates (it acts on proteins that are normally a target of the cytoplasmic tyrosine kinase Src).
29
Q

Homology Model of RET kinase domain and M918

A
30
Q

Hierarchical clustering of differentially expressed genes in tumours with MEN2A and MEN2B

A
  • Hierarchical clustering of differentially expressed genes identified by whole-genome gene chip analysis on NIH-RET(MEN2A) (C609Y, C634R), NIH-RET(MEN2B) (A883F, M918T) and NIH-RET(FMTC) (Y791F)-specific tumors.
  • Genes are colored according to the normalized expression values.
  • The colors in the heat map represent expression levels (red, overexpression; yellow, average expression; blue, underexpression/no expression).
  • The tumor samples are ordered in columns and the corresponding gene clusters in rows.
31
Q

Mechanisms Underlying the Activity of Oncogenic RET Mutations

A

(2020-21 BY2PA2) Molecular Pathology (13 decks)

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