Cancer, immune, skin, heart, gastrointestinal, fetal, and neuronal disorders

Paronychia; Folliculitis; Exanthem (RASH); Left ventricular outflow tract obstruction; Colonic disease; Placenta accreta; Troyer syndrome; Polycystic kidney disease, Type 1

Paronychia is related to lung cancer and is characterized by bacterial or fungal infections in the nails. Folliculitis can affect bone, bone marrow, and skin. Folliculitis can affect one or more follicles with an inflammatory response on anywhere but the feet or hands. Exanthem is irritated or swollen skin arising from contact with an irritant. Left Ventricular Outflow tract Obstruction is a hypertensive heart disease that can also affect liver and lung tissues. Colonic Disease can include ulcerative colitis (colon ulcers), rectum diverticulitis (inflammation leading to irritable bowel syndrome), and colorectal cancer colonic polyps. Placenta Accreta arises from the placenta attaching itself to the myometrium rather than endometrium. Placenta Accreta can lead to sepsis. Troyer Syndrome is a rare neuronal disease that induces muscle stiffness, leading to paralysis of the lower body. Polycystic Kidney Disease, Type 1 (PKD1) is related to the cystic kidney disorder.
 

Lung cancer (LC), EGFR-related; Lung cancer (LC); Breast cancer; Pancreatic cancer; Glioblastoma multiforme; Adenocarcinomas; Astrocytomas; Giant cell glioblastomas (GBM); Prostate cancer; Non-small cell lung carcinomas (NSCLC); Oligodendroglioma; leukemias; Brain cancer; Paronychia; Colon cancer; Renal cell carcinomas (RCC); Adenosquamous carcinomas; Pulmonary blastomas; Malignant peritoneal mesotheliomas; Blastomas; Adenocarcinomas in Situ; Lip cancer (lower); Sinonasal undifferentiated carcinomas (SNUC); Cervical adenosquamous carcinomas; Ring chromosome 7 (R7); Transitional cell carcinomas (TCC); Primary peritoneal carcinomas (PPC); Sweat gland carcinomas; Placental site trophoblastic tumours (PSST); Pleomorphic xanthoastrocytomas (PXA); Thymic epithelial neoplasms (TEN); Lymphoepithelioma-like carcinomas (LELC); Mammary Paget's disease; Hidradenomas; Colonic disease; Pancreatic endocrine carcinomas; Hidradenocarcinomas; Intraocular melanomas; Nonpapillary renal cell carcinomas; Microglandular adenosis is a breast cancer; Congenital pulmonary airway Malformation (CCAM); Basaloid squamous cell carcinomas; Gemistocytic astrocytomas; Superior vena cava syndrome (SVCS); Papillary glioneuronal tumours (PGNT); Brain stem gliomas; Ethmoid sinus adenocarcinomas; Lung cancer (LC) susceptibility; Orbital lymphangiomas; Spinal chordomas; Esophageal basaloid squamous cell carcinomas; Brain ependymomas; Gliosarcomas; Lung adenocarcinomas

EGFR 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. EGFR mutations have been linked to Glioblastoma Multiforme, which is related to astrocytoma and anaplastic astrocytoma, with regions of anaplastic cells surrounding necrotizing tissue. Glioblastoma Multiforme affects brain, endothelial, and bone tissues. Astrocytoma is the development of cancer arising from a glial cell, typically in the cerebrum, but often in the spinal cord as well. Oligodendroglioma can affect brain, spinal cord, and endothelial tissues and is a cancer arising from oligodendrocytes. Paronychia is related to lung cancer and is characterized by bacterial or fungal infections in the nails. Adenosquamous Carcinoma is a cancer that can arise from squamous cells and gland-like cells. Pulmonary Blastoma can arise either from lung tissue or from the pleura tissue which lines the chest cavity, covering the lungs. Malignant Peritoneal Mesothelioma is rare, and is characterized by edema, or collection of watery fluids in the lower limbs. Malignant Peritoneal Mesothelioma can affect the lung, colon, and lymph nodes as well. Sinonasal Undifferentiated Carcinoma is a rare cancer that develops in the sinus from rapid expansion of epithelial tissue. SNUC can lead to blocked breathing. Ring Chromosome 7 (R7) is a rare disease, and involves ERK signalling and PI-3K cascade signalling pathways in its development of disease. R7 can affect T cells, heart, and skin. Transitional Cell Carcinoma (TCC) is a cancer of the urinary system, affecting the kidney, urinary bladder, prostate, and ovary. Primary Peritoneal Carcinoma is a cancer of the peritoneal cavity and can affect the ovary, endothelial, and breast tissues. Sweat Gland Carcinoma is a tumour arising from sweat gland cells and can affect breast, skin, and lymph node tissues. Placental Site Trophoblastic tumour can induce spontaneous abortions (miscarriages), and is a gestational trophoblastic disease. Pleomorphic Xanthoastrocytoma is a rare brain cancer that primarily affects children and teenagers. Thymic Epithelial Neoplasm (TEN) is a cancer related to breast cancer and thymic epithelial tumours. TEN is a rare disease and can affect thymus, lung, and endothelial tissues. Lymphoepithelioma-Like Carcinoma is a tumour arising from the endothelium. Mammary Paget's Disease is a rare cancer of the nipple. Hidradenoma are benign tumours of sweat glands that can also affect skin, breast, and salivary gland tissues. Colonic Disease can include ulcerative colitis (colon ulcers), rectum diverticulitis (inflammation leading to irritable bowel syndrome), and colorectal cancer colonic polyps. Hidradenocarcinoma is a rare disease arising from unregulated tissue growth in sweat glands and development of a tumour. Intraocular Melanoma is a rare eye cancer arising from the pigment-producing cells (melanocytes) which reside in the uveal tract. Congenital Pulmonary Airway Malformation is related to mucoepidermoid carcinoma and adenocarcinoma and can lead to lung failure. Basaloid Squamous Cell Carcinoma is a cancer of the squamous cells (outer layer of skin). Gemistocytic Astrocytoma is a rare cancer related to astrocytoma and subependymal giant cell astrocytoma. Superior Vena Cava Syndrome (SCVS) is a rare disease obstructing blood flow into the superior vena cava (artery supplying the upper portion of the heart), and this disease is related to lung and breast cancer. Papillary Glioneuronal tumour is related to neuronitis and siderosis. Ethmoid Sinus Adenocarcinoma is related to the inverted papilloma and adenocarcinoma diseases. Orbital Lymphangioma is a rare lymphoma that can affect retinal and endothelial tissue. Brain Ependymoma is a neuronal cancer disease. Gliosarcoma is also a neuronal cancer disease, though it is rare and it arises from glial cells. lung Adenocarcinoma is a rare cancer partly characterized by its large production of mucus and which is associated with adenocarcinoma and lung cancer. Tissues affected by lung Adenocarcinoma include lung, brain, and endothelium.
 

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: Brain glioblastomas (%CFC= -76, p<0.0004); Brain oligodendrogliomas (%CFC= -96, p<0.0001); Breast epithelial carcinomas (%CFC= -56, p<0.011); Clear cell renal cell carcinomas (cRCC) (%CFC= +291, p<0.012); Head and neck squamous cell carcinomas (HNSCC) (%CFC= +118, p<0.006); Ovary adenocarcinomas (%CFC= +367, p<0.006); Prostate cancer - primary (%CFC= +103, p<0.0001); and Skin melanomas - malignant (%CFC= -69, p<(0.0003). The COSMIC website notes an up-regulated expression score for EGFR in diverse human cancers of 681, which is 1.5-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 4 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 support a role for this protein kinase in mouse cancer oncogenesis. Autophosphorylation of the EGFR can be fully inhibited with a R429E mutation. Autophosphorylation of the EGFR can be reduced with the Y275A (when associated with R309A), F287A (when associated with R309A), R309S (when associated with Y275A and F287A), and V689A mutations. Phosphorylation of EGFR can be fully inhibited with any of the N700A, L704A, R705A, I706A, and K745AM mutations. Reduced phosphorylation of EGFR can occur with the L688A, E690A, L692A/P, T693D, P694A, P699A, D974A, and R977A mutations. Increased phosphorylation of EGFR can occur with a T693A mutation. EGF binding to EGFR is promoted with the D587A+H590A, or K609A mutations. Constitutive activation of EGFR leading to constitutive downstream kinase activity has been seen with the mutations of V689M, E1005R+D1006K. A 50% decrease in interaction with PIK3C2B has been noted with an EGFR mutation of Y1016F. The interaction is decreased by 65% when the Y1016F mutation is associated with Y1197F. This interaction is fully inhibited with the mutations resulting in Y1197F and Y1092F. The Y1092F mutation alone will not affect the EGFR interaction with PIK3C2B, but will fully inhibit interactions when associated with F-1197 and F-1016 mutations. The Y1197F mutation alone will not affect the EGFR interaction with PIK3C2B, but when associated with Y1016F the EGFR-PIK3C2B interaction is inhibited by 65%, and when associated with Y1016F and Y1092F the interaction is fully inhibited. Interaction between EGFR and CBLC is heavily impaired with a R1068G mutation, and fully impaired with an Y1069F mutation.

Percent mutation rates per 100 amino acids length in human cancers: 1.53 % in 130410 diverse cancer specimens. This rate is 20.4-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: 2.36 % in 80494 lung cancers tested; 0.64 % in 142 peritoneum cancers tested; 0.52 % in 3730 central nervous system cancers tested; 0.33 % in 894 endometrium cancers tested; 0.33 % in 5136 large intestine cancers tested; 0.32 % in 1577 stomach cancers tested; 0.28 % in 1304 prostate cancers tested; 0.27 % in 2102 skin cancers tested; 0.18 % in 688 biliary tract cancers tested; 0.18 % in 3551 upper aerodigestive tract cancers tested; 0.17 % in 2160 oesophagus cancers tested; 0.17 % in 1822 ovary cancers tested; 0.13 % in 834 urinary tract cancers tested; 0.09 % in 4418 breast cancers tested; 0.09 % in 2966 haematopoietic and lymphoid cancers tested; 0.09 % in 1933 kidney cancers tested; 0.09 % in 1452 thyroid cancers tested.

Most frequent mutations with the number of reports indicated in brackets: L858R (9181); T790M (1093); G719A (166); G719S (115).

Over 3000 deletions mutations at E746, over 100 insertion mutations clustered between D770 and H773, and over 600 complex mutations around E746 and L747 are noted on the COSMIC website. These mutations are clustered in the first quarter of the kinase catalytic domain of the EGFR.