Cancer, reproductive disorders

Dosage-sensitive sex reversal

Dosage-sensitive sex reversal is a genetic disease characterized by the sex reversal of individuals with a normal 46,XY karyotype. This disease can result in a genetic male developing female external genitalia. Dosage-sensitive sex reversal can be the result of several different mechanisms, including mutations in the SRY gene, the overexpression of AHC due to Xp duplication, mutations in the SF-1 gene, or the underexpression of SOX9 and WT1.
 

Glioblastomas; Glioblastoma multiforme (GBM)

TRRAP may be an oncoprotein (OP). TRRAP mediates the transcriptional activation induced by the adenovirus E1A, which is a known viral oncoprotein that de-regulates the expression of several critical genes in mammalian cells leading to cancer formation. In addition, TRRAP plays a critical role in the regulation of MYC activation, a known oncogene, and is involved in MYC-mediated cell transformation. Furthermore, the TRRAP protein is predicted to be necessary for control of the mitotic checkpoint and cell cycle progression. Several mutations in the TRRAP gene have been observed in human cancers. Specifically, the S722P substitution mutation has been frequently observed in cutaneous malignant melanoma cells, indicating a causal pathogenic role for the mutated protein. Knockdown of the mutant S722P TRRAP protein with siRNA in melanoma cancer cells results in increased apoptosis, indicating that the mutant TRRAP protein is essential for melanoma cell survival and tumour progression. Therefore, the TRRAP protein displays oncogenic activity in the melanoma cells. In animal models, Cre-lox mediated knockdown of TRRAP expression lead to reduced cell proliferation due to the failure to sustain mitotic activity and cell-cycle progression, confirming the necessity of TRRAP for the regulation of the mitotic checkpoint and normal progression through the cell cycle.
 

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= +119, p<0.012); Bladder carcinomas (%CFC= +118, p<0.0001); and Skin melanomas - malignant (%CFC= +113, p<0.0007). The COSMIC website notes an up-regulated expression score for TRRAP in diverse human cancers of 717, which is 1.6-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 113 for this protein kinase in human cancers was 1.9-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 25077 diverse cancer specimens. This rate is only -11 % lower 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: 0.29 % in 923 skin cancers tested; 0.26 % in 10 peritoneum cancers tested; 0.25 % in 589 stomach cancers tested; 0.25 % in 1437 large intestine cancers tested; 0.17 % in 603 endometrium cancers tested; 0.17 % in 15 pituitary cancers tested; 0.11 % in 1637 lung cancers tested; 0.1 % in 548 urinary tract cancers tested; 0.1 % in 273 cervix cancers tested; 0.08 % in 1512 liver cancers tested; 0.07 % in 710 oesophagus cancers tested; 0.05 % in 833 ovary cancers tested; 0.05 % in 238 bone cancers tested; 0.04 % in 881 prostate cancers tested; 0.04 % in 1062 upper aerodigestive tract cancers tested; 0.03 % in 382 soft tissue cancers tested; 0.03 % in 2082 central nervous system cancers tested; 0.03 % in 1316 breast cancers tested; 0.03 % in 1276 kidney cancers tested; 0.02 % in 2010 haematopoietic and lymphoid cancers tested; 0.02 % in 127 biliary tract cancers tested; 0.01 % in 558 thyroid cancers tested; 0.01 % in 441 autonomic ganglia cancers tested; 0.01 % in 1459 pancreas cancers tested.

Most frequent mutations with the number of reports indicated in brackets: S722F (16); K159E (7); R1321M (4); P1136S (3); A1304T (3); R1706H (3).

Only 7 deletions, 4 insertions and no complex mutations are noted on the COSMIC website.