Cancer, developmental disorders

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH); Megalencephaly; Hemimegalencephaly; Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH), somatic; Corpus callosum agenesis

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) is a rare developmental disorder characterized by polydactyly, high forebrain and ventricular septal defects, and defective inter-ventricular communication. Megalencephaly is a rare growth and developmental disorder characterized by an abnormally large brain thought to result from a disturbance in the regulation of cell proliferation during brain development. Hemimegalencephaly is an extremely rare developmental disorder characterized by the unilateral enlargement of the cerebral hemispheres. Agenesis of the corpus callosum is a disease characterized by the partial or complete absence of the corpus callosum, the brain structure connecting the two hemispheres. The effects of MPPH can range from mild to severe, depending on other brain defects associated with the disease. Deletion mutations of the 1q42-q44 chromosomal region have been linked to various developmental disorders of the brain, including agenesis of the corpus callosum and microcephaly, and have been suggested as a contributor factor in the pathogenesis of MPPH. A known breakpoint for this deletion is located 20 kb upstream of the Akt3 gene, which indicates effects on gene function/regulation by the deletion. During human development, Akt3 expression is elevated in the cortex at 9-weeks gestation, a period characterized by active neurogenesis. In addition, several substitution mutations in the Akt3 gene have been reported in patients with MPPH, including R465W, N229S, and E17K. Interestingly, the E17K mutation has also been observed in breast cancer and is thought to cause a gain-of-function of protein activity. In animal studies, mice lacking brain specific Akt3 expression during neural development display a 20% smaller brain size compared to wildtype as well as abnormal development of the corpus callosum. These abnormalities are attributed to reduced cell proliferation and closely resembled the pathological phenotype of corpus callosum agenesis as seen in humans. Brain tissue samples from Akt3 deficient mice displayed reduced levels of mTOR (mammalian target of rapamycin) activation. Furthermore, the mouse Nmf350 mutation phenotype was attributed to a D219 substitution mutation in the kinase catalytic domain of the Akt3 gene. Enzymatic analysis of the mutant kinase in HEK293 cells revealed significantly increased kinase catalytic activity as compared to wildtype protein. The Nmf350 mouse model, characterized by low seizure threshold, brain enlargement, and ectopic neuronal development in the dentate hilus and molecular layer of the hippocampus, was identified from a phenotype-driven mutagenesis screen and is used as a model for neurological disorders. This demonstration further supports a role for abnormal Akt3 activity as a contributor in the pathology of neurological development disorders, such as MPPH.
 

Thymoma

AKT3 appears to be an oncoprotein (OP) based on its similarity to Akt1 and Akt2, although it does not display a higher than normal rate of mutation in human tumours. The active form of the protein kinase normally acts to promote tumour cell proliferation. AKT3 has been implicated as a key modulator in several human cancer types, including melanomas, gliomas, ovarian cancer, and breast cancer. AKT3 promotes cancer progression through a gain-of-function in the apoptosis suppressive activity of the enzyme, leading to aberrant cell growth. Expression levels of AKT3 have been shown to increase throughout the course of melanoma tumor progression, peaking in advanced-stage metastatic melanomas. Mutations in the AKT3 gene have been observed in several melanoma cell lines, including an activating E17K substitution mutation similar to that seen in the AKT1 gene in human colorectal cancers. However, the E17K mutation is relatively rare in AKT3 in human tumours. Moreover, like AKT2, there are no predominent mutations in AKT3 in human cancers, with a relatively dispersed pattern of low level mutations through out the full length of the protein. AKT3 is also known to play a pivotal role in the development of ovarian cancer through its role in the regulation of the G2/M phase transition of the cell cycle. Along with AKT2, AKT3 is also important in the formation and progression of glioblastomas. In addition, a fusion gene involving AKT3 has been identified in breast cancer tissue samples. The MAGI3/AKT3 fusion gene was recurrently identified in triple-negative breast cancer specimens, which lack estrogen receptors, progesterone receptors, and ERBB2 expression. The fusion gene results in constitutive activation of the AKT3, and suppresses apoptosis and stimulates aberrant cell growth and enhanced survival.
 

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= -46, p<0.052); Colorectal adenocarcinomas (early onset) (%CFC= +136, p<0.001); Oral squamous cell carcinomas (OSCC) (%CFC= +175, p<0.005); Ovary adenocarcinomas (%CFC= -64, p<0.0007); Skin melanomas - malignant (%CFC= +64, p<0.002); The COSMIC website notes an up-regulated expression score for AKT3 in diverse human cancers of 612, which is 1.3-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 16 for this protein kinase in human cancers was 0.3-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: 0.09 % in 26137 diverse cancer specimens. This rate is only 24 % 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: 0.4 % in 1241 large intestine cancers tested; 0.39 % in 648 endometrium cancers tested; 0.35 % in 589 stomach cancers tested; 0.28 % in 910 skin cancers tested; 0.23 % in 1941 lung cancers tested.

None >3 in 21235 cancer specimens

Only 1 deletion, and no insertions or complex mutations are noted on the COSMIC website.