Cancer, gastrointestinal, nephrological, endocrine, eye, ear, cardiovascular, and skin disorders

Hirschsprung's disease; Ret-related Hirschsprung disease; Ret-related Pheochromocytoma; Ret-related renal Adysplasia; Renal agenesis; Congenital central hypoventilation syndrome; Renal hypoplasia, Isolated; renal hypodysplasia/aplasia 1; Pheochromocytoma, modifier of; Central hypoventilation syndrome; Congenital, with or without Hirschsprung disease; Wagenmann-Froboese syndrome; Hyperparathyroidism; Neurofibromatosis; Von Hippel-Lindau disease; Cowden disease; Unilateral renal agenesis; Hypoganglionosis; Lichen amyloidosis; Medullary sponge kidney; Hereditary paraganglioma-pheochromocytoma syndromes; Intestinal obstruction; Familial Isolated hyperparathyroidism; Primary cutaneous amyloidosis; Renal dysplasia; Struma ovarii; Parathyroid gland disease; Sipple syndrome; Thyroiditis

Mutations of this gene are associated with Hirschsprung disease 1, which is characterized by absence of enteric ganglia along a variable length of the intestine. R67H, R114H, A432E and P1039L substitutions are involved in congenital central hypoventilation syndrome, that often shows abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. It may also associate with renal abnormalities.
 

Multiple endocrine neoplasia (MEN); Pheochromocytomas (PCC); Thyroid cancer (TC); Multiple endocrine neoplasias (MEN) type 2a; Thyroid medullary carcinomas (MTC); Papillary carcinomas (PTC); Familial medullary thyroid carcinomas (FMTC); Paraganglioma (PGL); Papillary thyroid carcinomas (PTC); Follicular adenoma (FA); Follicular thyroid carcinomas (FTC); Primary peritoneal carcinomas (PPC); Pancreatic islet cell tumours; Sacrococcygeal teratoma (SCT); Peritoneal carcinomas; Familial papillary thyroid carcinomas (fPTC); neuroblastomas (NB)

RET is a known oncoprotein (OP). Cancer-related mutations in human tumours point to a gain of function of the protein kinase. The active form of the protein kinase normally acts to promote tumour cell proliferation. Mutations in the Ret gene are associated with the disorders multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, and medullary thyroid carcinoma. Ret was identified as a potential low-penetrance gene for apparently sporadic pheochromocytoma.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Bladder carcinomas (%CFC= -48, p<0.006); Brain glioblastomas (%CFC= -92, p<0.048); Breast epithelial carcinomas (%CFC= +253, p<0.068); Breast non-basal-like cancer (BLC) (%CFC= +49, p<(0.0003); Skin fibrosarcomas (%CFC= +468, p<0.003); and Skin melanomas (%CFC= -51, p<0.048). The COSMIC website notes an up-regulated expression score for RET in diverse human cancers of 348, which is 0.8-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 0 for this protein kinase in human cancers was 100% lower than the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.28 % in 34161 diverse cancer specimens. This rate is 3.75-fold higher than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 2.29 % in 2675 thyroid cancers tested; 0.5 % in 1528 large intestine cancers tested; 0.3 % in 1378 skin cancers tested; 0.23 % in 856 stomach cancers tested; 0.22 % in 708 endometrium cancers tested; 0.22 % in 534 urinary tract cancers tested; 0.18 % in 2555 lung cancers tested; 0.13 % in 696 oesophagus cancers tested; 0.07 % in 1316 kidney cancers tested; 0.05 % in 2832 breast cancers tested; 0.05 % in 2130 haematopoietic and lymphoid cancers tested.

Most frequent mutations with the number of reports indicated in brackets: M918T (496); C634R (33); C634Y (19); C634W (16).

In human tumours, there are two main regions of point mutations: one small cluster at amino acid residues 591-634 and a slightly larger cluster around M918 with many point mutations. Over 30 deletions (15 at E632 and 10 at D898), 2 (1 at C634) insertions and over 20 complex mutations (17 at E632) are also noted on the COSMIC website.