Prevalence of RET fusions in human cancer.
Abstract
The rearranged during transfection (RET) proto-oncogene encodes a transmembrane receptor tyrosine kinase and its alterations cause various cancers and developmental disorders. Gain-of-function mutations caused by gene rearrangements have been found in papillary thyroid carcinoma, non-small-cell lung carcinoma, and other cancers, while point mutations are responsible for hereditary cancer syndrome, multiple endocrine neoplasia type 2, and sporadic medullary thyroid carcinoma. Loss-of-function point mutations or deletions lead to Hirschsprung disease, a developmental disorder associated with aganglionosis of the intestinal tract. RET is also involved in various physiological and developmental functions through activation by glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs). Gene knockout studies have revealed that GDNF-RET signaling plays an essential role in the development of the enteric nervous system, kidney, and urinary tract, as well as in the self-renewal of spermatogonial stem cells. Moreover, recent progress in developing RET-selective inhibitors has significantly contributed to treating patients with RET-altered cancers. This chapter describes and discusses the functions associated with disease and physiology.
Keywords
- RET proto-oncogene
- glial cell line-derived neurotrophic factor
- thyroid cancer
- non-small-cell lung cancer
- Hirschsprung’s disease
1. Introduction
The rearranged during transfection (
Alterations in the
2. Structure and expression of RET proto-oncogene
The
RET expression is observed in the developing excretory and nervous systems during the embryogenesis of mice and rats [10, 11]. It is highly expressed in the nephric duct, ureteric bud, and collecting ducts of developing kidneys. RET is also expressed in enteric neural crest-derived cells, the autonomic and dorsal root ganglia of the peripheral nervous system, the neuroepithelial cells of the ventral neural tube, and several cranial ganglia in the central nervous system. In agreement with this expression pattern,
3. Activation of RET by glial cell line-derived neurotrophic factor (GDNF)-family ligands
In 1993, GDNF was purified and cloned as a neurotrophic factor that enhances the survival of midbrain dopaminergic neurons [12]. GDNF has also been shown to be a potent trophic factor for spinal motor and central noradrenergic neurons. Additionally, GDNF is essential for the survival and differentiation of peripheral sympathetic, parasympathetic, sensory, and enteric neurons. GDNF is structurally related to the transforming growth factor (TGF)-β and contains seven cysteine residues called cysteine knot motifs. Furthermore, three other proteins of the GDNF family ligands (GFLs), including neurturin (NRTN), artemin (ARTN), and persephin (PSPN), were identified, sharing approximately 40% amino acid identity with each other and possessing neurotrophic effects on various neurons [3].
Physiologically, RET is activated by GFLs through a unique multicomponent receptor complex consisting of a glycosylphosphatidylinositol-anchored co-receptor (GDNF family receptor α 1–4, GFRα1–4) as a ligand-binding component and RET tyrosine kinase as a signaling component (Figure 1). The formation of the GFL-GFRα-RET 2:2:2 ternary complex results in the activation of various intracellular signaling pathways necessary for physiological function [13, 14, 15]. GDNF, NRTN, ARTN, and PSPN use GFRα1, GFRα2, GFRα3, and GFRα4, respectively, as their preferred ligand-binding receptors (Figure 1), although crosstalk occurs between the ligand and co-receptor pairs to a certain extent [16, 17]. Despite the crosstalk demonstrated
More recently, another ligand of the TGF-β superfamily, growth differentiation factor 15 (GDF15), has been shown to bind to GFRα-like (GFRAL) and activate RET (Figure 1), regulating food intake and body weight [21, 22, 23, 24]. GDF15 is a stress-induced hormone, and its plasma levels are markedly increased in various human diseases, including cardiovascular and chronic kidney diseases, diabetes, advanced cancer, and serious infections. Co-expression of GFRAL and RET was detected in neurons of the hindbrain area postrema and the nucleus of the solitary tract, where RET activation by GDF15 plays a pivotal role in body weight control.
4. Activation of RET intracellular signaling pathways by GFLs and their roles in the development
Following RET activation by GFLs, many tyrosine residues in the intracellular region are phosphorylated, activating various signaling pathways. The intracellular region of RET contains 18 tyrosine residues, two of which are in the juxtamembrane domain, 11 in the kinase domain, and five in the C-terminal region. Of the five tyrosine residues in the C-terminus, three (Y1015, Y1029, and Y1062) were common between RET9 and RET51, and two (Y1096 and Y1102) were present only in RET51. Each phosphorylated tyrosine interacts with specific adaptor proteins. For example, phosphorylated Y981, Y1015, Y1062, and Y1096 represent binding sites for SRC, phospholipase Cγ (PLCγ), SHC/FRS2/DOK1–6/IRS1–2, and GRB2, respectively (Figure 2). The signal transducer and activator of transcription 3 (STAT3) bind to phosphorylate Y752 and Y928 [3, 17]. As a result, the RAS/mitogen-activated protein kinase and/or phosphatidylinositol-3 kinase pathways were activated through the phosphorylation of Y1062 or Y1096 (Figure 2). Activation of the PLCγ pathway through phosphorylated Y1015 regulates protein kinase C activity and Ca2+ release from the endoplasmic reticulum, increasing intracellular Ca2+ levels and inducing Ca signaling.
The importance of each intracellular signaling pathway has been demonstrated in mouse gene-targeting studies.
HSCR is a relatively common congenital malformation associated with aganglionosis of the gastrointestinal tract (prevalence: one in 5000 live births). The disease is characterized by the absence of the intramural nervous plexuses, myenteric plexus (Auerbach plexus), and submucosal plexus (Meissner plexus).
5. RET rearrangement in human cancer
In human cancers,
Further studies reported that the prevalence of
The most prevalent fusion genes were coiled-coil domain containing 6 (
Cancer | Prevalence | |
---|---|---|
Papillary thyroid carcinoma in general population | 5–20% | |
Papillary thyroid carcinoma after Chernobyl reactor accident | 50–80% | |
Non-small cell lung carcinoma | 1–2% | |
Colon carcinoma | ~0.2% | |
Salivary intraductal carcinoma | ~40% |
The prevalence of
Next-generation DNA and RNA sequencing technologies have identified less frequent
6. RET mutations in MEN2 and sporadic cancer
Medullary thyroid carcinoma (MTC) is a malignant tumor of the neural crest-derived parafollicular C cells that produce calcitonin. MTC develops either sporadically (~75% of cases) or as a component of the hereditary cancer syndrome MEN2 (~25% of cases). MEN2 is an autosomal-dominant cancer syndrome characterized by the development of MTC and pheochromocytoma derived from adrenal chromaffin cells. Based on clinical phenotypes, MEN2 is classified into three subtypes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). The affected family members by MEN2A develop MTC (~100% of cases), pheochromocytoma (~50% of cases), and parathyroid hyperplasia/adenoma (hyperparathyroidism, ~20% of cases). Lichen amyloidosis is occasionally observed in MEN2A patients. MEN2B is a more aggressive subtype with early onset of MTC (~100%) and pheochromocytoma (~50%). In addition, MEN2B patients display a more complex phenotype, including mucosal neuroma, hyperganglionosis of the intestine, medullated corneal nerve, and marfanoid habitus, but not hyperparathyroidism. FMTC is characterized by MTC, which usually develops later in life and is now considered an indolent subtype of MEN2A.
Germline
We and others have demonstrated that cysteine mutations in MEN2A or FMTC result in ligand-independent constitutive activation (dimerization) of mutant RET by forming aberrant intermolecular disulfide bonds (Figure 3B). Cysteine residues are thought to form the intramolecular disulfide bonds necessary for the appropriate tertiary structure of the RET protein. The hypothesis is that when a cysteine residue is replaced with a non-cysteine residue by
Two specific missense mutations, Met918Thr (M918T) and Ala883Phe (A883F), were associated with the development of MEN2B (Figure 3A). The M918T mutation accounts for more than 95% of MEN2B patients, while fewer than 4% are accounted for by the A883F mutation [3, 31]. In addition, double germline mutations at codons 804 and 806 (V804M and Y806C) were found in a Japanese patient with clinical features characteristic of MEN2B [52].
According to data published in a public database in 2015 (COSMIC; Catalog of Somatic Mutations in Cancer), somatic
7. RET mutations in molecular diagnostic
8. RET overexpression in breast cancer
RET has been reported to be overexpressed in 40–60% of breast tumors across multiple tumor subtypes [55]. In particular, its expression is common in the estrogen receptor (ER)-positive subtype and is associated with larger tumor size, higher stage, and reduced overall survival. Elevated RET expression was also observed in ER-positive breast cancer cell lines, mirroring observations from patient samples. Treatment with estradiol induced the transcription of RET, GFRα, and ARTN, suggesting a regulatory mechanism for RET function. Multiple estrogen response elements have been identified within the
9. Development of selective RET kinase inhibitors for targeted therapy
Various tyrosine kinase inhibitors (MTKIs) have recently been used to treat
The RET-selective TKIs selpercatinib and pralsetinib have been developed to treat
In
As observed for inhibitors of other tyrosine kinases, resistance to selective RET inhibitors occurs
10. Conclusion
Since the discovery of the
In developmental biology, RET functions, including intracellular signaling, are being extensively studied to understand the mechanisms underlying the development of the enteric nervous system, kidneys, and spermatogenesis.
Moreover, recent findings demonstrating the association between RET activation by GDF15 in neurons of the brainstem and a decrease in food intake are opening up a new field of research [21, 22, 23, 24]. These findings may advance our understanding of the mechanisms underlying cachexia in patients with cancer. It is expected that future research on the RET function will continue to have a profound impact on life and medical science.
Acknowledgments
The author thanks all laboratory members and research collaborators for insightful discussion. Work at the author’s laboratory is partly supported by Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. I would like to thank Editage (www.editage.com) for English language editing.
Conflict of interest
The author declares no conflict of interest.
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