Cancer, endocrine disorders

Hyperinsulinemic hypoglycemia, familial, 5; Diabetes mellitus, Insulin-resistant, with acanthosis nigricans; Rabson-Mendenhall syndrome; Donohue syndrome; Diabetes mellitus, non-insulin-dependent, late onset; Hypertension, Insulin resistance-related; Alzheimer's disease; Myotonic dystrophy; Ovarian disease; Acanthosis nigricans; Hyperinsulinemic hypoglycemia; Obesity; Metabolic syndrome X; Hemi-hypertrophy; Congenital fiber-type disproportion; Myotonic dystrophy Type 2; Berardinelli-Seip congenital lipodystrophy; Acanthocytosis; Fetal macrosomia; Fasting hypoglycemia; Insulin autoimmune syndrome

Hyperinsulinemic hypoglycemia is a condition characterized by low blood glucose resulting from the excessive release of insulin. This disease can be acquired during life or inherited and can range in severity from life-threatenting to a mild nuissance. Diabetes mellitus, insulin resistance with acanthosis nigricans is a disease characterized by combined symptoms of diabetes, insulin resistance, and acanthosis nigricans. Acanthosis nigricans is characterized by the hyperpigmentation of the skin, producing a brown to black, poorly defined, and velvety region of skin, which is usually found in the posterior and lateral folds of the neck, the armpits, navel, forehead, groin, and other body folds. Donohue syndrome, also known as Leprechanumism, is an extremely rare genetic disease characterized by stunted growth, protruding ears, flaring nostrils, and thick lips. Rabson-Mendenhall syndrome is a genetic disease characterized by a severe resistance to insulin. Symptoms of the disease include growth retardation, hypertrophy of muscle and fat tissues, and craniofacial, dental, and skin abnormalities. Several mutations in the INSR gene have been observed in patients with diabetes mellitus, insulin resistance, with acanthosis nigricans, including substitution mutations (G1035V, R762S, W1227S, A1161T, N489S, R1020Q, A1162E, R1201Q) and nonsense mutations (W160X). These mutations are associated with a loss-of-function , as many of them are found within the kinase catalytic domain of the protein. It was observed that a patient with Donohue syndrome displayed an 80-90% reduction in the amount of INSR in circulating monocytes, and those present had a significantly decreased responsiveness to temperature and pH. In addition, a marked reduction in INSR mRNA has also been demonstrated in the circulating monocytes of a patient with Donohue syndrome. Several mutations in the INSR gene have been observed in patients with Donohue syndrome, including substitution mutations (K487E, L260P, H236R, G58R, V55A, G393R, R113P, W439S, I146M, N458D) and nonsense mutations (Q699X, R924X, R399X, K148X). These mutations are also associated with a loss-of-function of the protein. In addition, two mutations in the INSR gene were observed in patients with Rabson-Medenhall syndrome. One was a A-G transition at the 3-prime splice site of intron 4 resulting in a decreased mRNA expression and a severely truncated protein. The other mutation was an 8-bp deletion in exon 12 of the gene. This mutation also decreased mRNA levels and produced a truncated protein. Thus, the phenotype of this disease is associated with a defective INSR protein. Several animal studies have revealed links between INSR and disease phenotypes. For example, genetically obese mice with insulin resistance were shown to have a mutation in the INSR gene, which decreased the tyrosine kinase catalytic activity of the protein. In addition, ablation of all INSR in mice resulted in the development of severe hyperglycemia and hyperketonia within hours of birth, resulting in death due to diabetic ketoacidosis within 48-72 hours of birth.
 

Brain cancer

INSR appears to be an oncoprotein (OP). over activation of the insulin receptor signalling pathway has been linked to the development of several cancer types. Significantly elevated INSR expression is observed in a high percentage of samples representing several subtypes of breast cancer (e. g. luminal; 48. 1%, triple negative; 41. 9%, and HER2; 64. 3%, of 438 specimens). In addition, elevated INSR expression in breast cancer is correlated with poor patient survival. Expression of phosphorylated INSR, as well as phosphoryalted IGF-1R and its downstream signalling target phospho-S6, were observed in 438 cases of invasive breast cancer samples. In eight breast cancer cell lines it was demonstrated that IGF-2 binds to and activates the INSR protein with 63% of the potency of insulin. By contrast, in non-malignant human breast cells, IGF-2 has about 1% the potency of insulin in binding to INSR. This activation of INSR by IGF-2 in cancer cells at much higher potency than in normal cells is hypothesized to lead to cancer cell growth and represent a novel autocrine/paracrine signalling mechanism by which cancer cells can promote survival and proliferation. Additionally, elevated INSR expression has been reported in breast cancer cell lines, higher than in any normal tissue investigated, including the liver. The INSR protein in the cancer cell retained the ability to bind to and be activated by insulin. INSR expression in the cancer specimens was restricted to the epithelial cells of the breast and was not obsrved in either the stromal or inflammatory cells present in the tissue samples. Additionally, there was no correlation between INSR expression level, age, body weight, menopausal status, or nodal involvement.
 

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: Barrett's esophagus epithelial metaplasia (%CFC= +285, p<0.017); Breast epithelial hyperplastic enlarged lobular units (HELU) (%CFC= -59, p<0.011); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +281, p<0.007); Oral squamous cell carcinomas (OSCC) (%CFC= +70, p<0.082); Pituitary adenomas (aldosterone-secreting) (%CFC= +61, p<0.017); and Prostate cancer - primary (%CFC= +72, p<0.0001). The COSMIC website notes an up-regulated expression score for INSR 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 23 for this protein kinase in human cancers was 0.4-fold of 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: 0.07 % in 25404 diverse cancer specimens. This rate is only -5 % lower and is very similar to 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: 0.35 % in 864 skin cancers tested; 0.31 % in 1270 large intestine cancers tested; 0.24 % in 603 endometrium cancers tested; 0.21 % in 589 stomach cancers tested; 0.12 % in 710 oesophagus cancers tested; 0.12 % in 548 urinary tract cancers tested; 0.12 % in 238 bone cancers tested; 0.11 % in 1958 lung cancers tested; 0.08 % in 273 cervix cancers tested; 0.06 % in 891 ovary cancers tested; 0.06 % in 1512 liver cancers tested; 0.06 % in 1316 breast cancers tested; 0.06 % in 127 biliary tract cancers tested; 0.04 % in 1276 kidney cancers tested; 0.02 % in 942 upper aerodigestive tract cancers tested; 0.02 % in 939 prostate cancers tested; 0.02 % in 441 autonomic ganglia cancers tested; 0.02 % in 2082 central nervous system cancers tested; 0.02 % in 1467 pancreas cancers tested; 0.01 % in 558 thyroid cancers tested; 0 % in 2009 haematopoietic and lymphoid cancers tested.

Most frequent mutations with the number of reports indicated in brackets: A1340V (3).

Only 2 deletions, and no insertions or complex mutations are noted on the COSMIC website.