Cancer, neurological disorders

Wallerian degeneration; Charcot-Marie-Tooth disease Type 1a; Charcot-Marie-Tooth disease Type 1; Congenital pulmonary airway malformation

Wallerian degeneration, also known as anterograde degeneration, is the degeneration of the distal segment of an axon after separation from the cell body by axotomy (transection of an axon). A similar process occurs in certain neurodegenerative diseases (termed 'Wallerian-like degeneration'), particularly those with components of impaired axonal transport. Charcot-Marie-Tooth disease is an inherited neurological disease affecting the peripheral nervous system. Symptoms include weakness, atrophy of the muscles, and loss of peripheral sensation. This disease is inherited in an autosomal dominant manner. It is thought that the symptoms of this disease are attributable to the progressive degeneration of axons. Nerve biopses from affected individuals reveal segments of demyelination, schwann cell hyperplasia, and evidence of attempted remyelination. Progression of the disease is characterized by progressive Schwann cell loss, indicating further demyelination and axonal degeneration. Overexpression of ErbB2 has been reported in schwann cells in nerve biopses from patients with Charcot-Marie-Tooth disease, hypothesized to have a role in the failure of myelination by schwann cells or contribute to the axonal damage observed in the disease. Therefore, elevated expression of ErbB2 may have a role in the pathogenesis of Charcot-Marie-Tooth disease.
 

Breast cancer; Lung cancer (LC); Ductal carcinomas in situ; Uterine carcinosarcoma; Adenocarcinomas; Ovarian cancer; Medulloblastoma; Cholangiocarcinomas; Transitional cell carcinomas; Inflammatory breast carcinomas; Adenocarcinomas in situ; Pleomorphic adenoma; Primary peritoneal carcinomas; Sweat gland carcinomas; Placental site trophoblastic tumours; In situ carcinomas; Thymic epithelial neoplasm; Mammary Paget's disease; Hereditary diffuse gastric cancer; Breast fibroadenoma; Hidradenoma; Fallopian tube cancer; Diffuse gastric cancer; Pituitary carcinomas; Breast carcinomas in situ; Female breast carcinomas; Hidradenocarcinomas; Bile duct adenoma; Ovarian carcinosarcoma; Ewing's family of tumours; Microglandular adenosis; Sinonasal undifferentiated carcinomas; Nonseminomatous germ cell tumours; Papillary serous adenocarcinomas; Gastroesophageal junction adenocarcinomas; Glassy cell carcinomas of the cervix; Progesterone-receptor positive breast cancer; Lipid-rich carcinomas; Breast scirrhous carcinomas; neuroblastomas; Gastric cancer, somatic; Ovarian cancer, somatic; Adenocarcinomas of lung, somatic; Glioblastoma, somatic

ERBB2 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. Significantly elevated expression levels of ErbB2 is observed in many cancer types, including adenocarcinoma of the salivary gland, gastric cancer, ductal carcinoma, breast cancer, lung cancer, and ovarian cancer. Analysis of 120 primary lung tumours revealed that 4% had mutations in the ErbB2 catalytic domain, which was compared to a observed rate of 10% in lung adenocarcinoma cell lines. Several mutations in the ErbB2 gene have been observed in cancer patients, including a 4 amino-acid insertion at codon 774, a 3 amino-acid insertion at codon 779, and four substitution mutations (L755P, E914K, G776, N857S). However, gain-of-function mutations in ErbB2 that result in an over-active oncogenic protein are rarely seen in human cancers, insteadthe observed mutations are associated with an elevated expression of unmutated ErbB2. For example, ErbB2 expresion was observed to be ~20-30% higher in breast cancer cell lines compared to control breast tissue. For these cancer types, treatment with trastuzumab (Herceptin), an anti-ErbB2 antibody, has been demonstrated to be an effective anti-cancer treatment.
 

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= +190, p<0.024); Brain glioblastomas (%CFC= -56, p<0.031); Cervical cancer (%CFC= +88, p<0.079); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= -76, p<0.003); Gastric cancer (%CFC= +237, p<0.101); Oral squamous cell carcinomas (OSCC) (%CFC= -50, p<0.039); Ovary adenocarcinomas (%CFC= +67, p<0.056); and Skin melanomas - malignant (%CFC= -55, p<0.078). The COSMIC website notes an up-regulated expression score for ERBB2 in diverse human cancers of 697, which is 1.5-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 42 for this protein kinase in human cancers was 0.7-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.

Percent mutation rates per 100 amino acids length in human cancers: 0.11 % in 47546 diverse cancer specimens. This rate is a modest 1.4-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: 0.58 % in 716 urinary tract cancers tested; 0.33 % in 2040 large intestine cancers tested; 0.25 % in 1275 stomach cancers tested; 0.18 % in 1426 skin cancers tested; 0.14 % in 752 endometrium cancers tested; 0.13 % in 3036 breast cancers tested; 0.11 % in 14526 lung cancers tested; 0.09 % in 1748 ovary cancers tested; 0.09 % in 1389 pancreas cancers tested; 0.06 % in 1709 upper aerodigestive tract cancers tested; 0.06 % in 1356 kidney cancers tested; 0.05 % in 2277 haematopoietic and lymphoid cancers tested.

Most frequent mutations with the number of reports indicated in brackets: A775ins (54); S310F (43); L755S (32); R678Q (18); (V842I (17); V777L (9); D776Y (6).

Only 4 deletions over the full sequence, but 138 insertions (at A775) and 16 complex mutations (at G776) observed in the kinase domain are noted on the COSMIC website.