Cancer, cardiovascular disorders

Essential hypertension; Aortic valve stenosis; Hypertensive heart disease

Essential hypertension, also called idiopathic hypertension, is a disease characterized by elevated blood pressure that does not have an identifiable cause. This is the most common form of hypertension, accounting for ~95% of all cases. Aortic value stenosis (AVS) is a cardiovascular disease characterized by narrowing of the aortic valve, which reduces the outflow of blood from the heart. Symptoms include chest pain, fatigue, difficulty breathing, heart palpitations, and heart murmur. ANPa (NPR1) is a membrane-bound guanylate cyclase that functions as the receptor for both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which are potent vasoactive factors and central to cardiovascular homeostasis. ANPa is mainly expressed in the kidney, vascular tissue, and adrenal gland, and upon stimulation initiates natriuresis, diuresis, and vasodilation, which contribute to lowering blood pressure. Loss-of-function mutations in ANPa have been linked with elevated blood pressure and hypertensive diseases, as insensitivity to ANP released from the heart tissue leads to the sustained elevation of blood pressure. Different allelic variants of the ANPa gene have been shown to be associated with an increased risk of hypertension. Specifically, individuals homozygous for a length polymorphism of the ANPa gene (referred to as the 3C allele) at the 15129 position in the 3'-untranslated region of the gene were shown to have significantly higher systolic blood pressure and a prolonged relaxation time of the left ventricular myocardium following isometric contraction. In animal studies, mice lacking ANPa displayed elevated blood pressure, cardiac muscle hypertrophy, and interstitial fibrosis, which are similar to the symptoms of human hypertensive disease. Additionally, echocardiographic analysis of the mice revealed systemic hypertension. All of these mice experienced sudden death, characterized by congestive heart failure and in some cases aortic dissection. Additionally, histological analysis of cardiac tissue from mice lacking cardiomyocyte specific expression of ANPa revealed cells that were ~20% larger than wildtype, a phenotype that was reduced upon the introduction of ectopic ANPa expression. Therefore, loss-of-function mutations in ANPa may contribute to the pathogenesis of hypertension.
 

Colon adenocarcinomas; Breast adenocarcinomas

ANP-alpha R may be an oncoprotein (OP) and a tumour suppressor protein (TSP). Significantly elevated levels of ANPa protein expression has been observed in several human cancers and gain-of-function mutations in the ANPa gene have been implicated in tumorigenesis. However, the specific functional role of natriuretic peptides in human cancer remains unclear. In animal studies, mice lacking functional ANPa do not permit the growth of implanted human lung cancer, melanoma, or ovarian cancer cells, in contrast to control mice. Hypermethylation of the ANPa gene was reported in 42. 5% of gastric cancer tissue samples, although the exact relevance of this result to cancer progression is not well understood. Methylation of the ANPa gene was also correlated with lymph node metastasis. Additionally, reduced expression of ANPa in human colorectal cancer specimens was found to be correlated with significantly increased patient survival times.
 

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: Lung adenocarcinomas (%CFC= -64, p<0.0001); Ovary adenocarcinomas (%CFC= +75, p<0.029); Pituitary adenomas (aldosterone-secreting) (%CFC= +53, p<0.039); Skin melanomas - malignant (%CFC= -83, p<0.002); Skin squamous cell carcinomas (%CFC= -58, p<0.041); Uterine fibroids (%CFC= -59, p<0.007); Uterine leiomyomas from fibroids (%CFC= -69, p<0.002); and Vulvar intraepithelial neoplasia (%CFC= -51, p<0.019). The COSMIC website notes an up-regulated expression score for ANP-a in diverse human cancers of 399, which is 0.9-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 5 for this protein kinase in human cancers was 0.1-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: 0.08 % in 24783 diverse cancer specimens. This rate is very similar (+ 6% higher) 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: 0.4 % in 864 skin cancers tested; 0.27 % in 589 stomach cancers tested; 0.27 % in 1270 large intestine cancers tested; 0.17 % in 1635 lung cancers tested; 0.16 % in 603 endometrium cancers tested; 0.1 % in 942 upper aerodigestive tract cancers tested; 0.09 % in 1512 liver cancers tested.

Most frequent mutations with the number of reports indicated in brackets: V510G (6); R798C (3).

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