Cancer, developmental disorders

Cerebellar agenesis

Cerebellar Agenesis is a rare disorder that has been related to diabetes mellitus, permanent neonatal, with cerebellar agenesis and to the hydrocephalus disorder. Cerebellar Agenesis is characterized by the complete lack of cerebellum causing impaired motor control.
 

Papillary thyroid carcinomas (TPC); Follicular thyroid carcinomas (FTC); 8p11 myeloproliferative syndrome

TIF1a is linked to Papillary Thyroid Carcinomas (TPC),which are rare thyroid (endocrine) cancers that affect women more often than men. TPC is characterized by the development of irregular, finger-like extensions of fibrous stroma covered in a layer of neoplastic epithelial cells. Follicular Thyroid Carcinoma (FTC) is another form of thyroid cancer and can affect pituitary and skin tissues in addition to the thyroid. 8p11 Myeloproliferative Syndrome is a rare blood cancer forming either myeloid or lymphoid cell cancer. TIF1A can form an oncogene when it is fused with RET. A D827A mutation in TIF1a resulted in decreased affinity for any histone H3 not methylated at Lys-4. Interaction with histone H3 can be fully inhibited through a C840W mutation. Interaction of TIF1a with H3 histones acylated at Lys-23 is strongly reduced with the F979A + N980A mutations, in conjunction.
 

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= +169, p<0.004); Brain glioblastomas (%CFC= -64, p<0.0001); Brain oligodendrogliomas (%CFC= -79, p<0.0001); Colon mucosal cell adenomas (%CFC= +62, p<0.0002); Oral squamous cell carcinomas (OSCC) (%CFC= +47, p<0.019); and Ovary adenocarcinomas (%CFC= +109, p<0.006).

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis. A D827A mutation in TIF1a can result in decreased affinity for any histone H3 not methylated at Lys-4. Interaction with histone H3 can be fully inhibited through a C840W mutation. Interaction of TIF1a with H3 histones acylated at Lys-23 can be strongly reduced with the F979A + N980A mutations, in conjunction.

Percent mutation rates per 100 amino acids length in human cancers: 0.07 % in 25259 diverse cancer specimens. This rate is only -9 % lower and is very similar 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 1229 large intestine cancers tested; 0.32 % in 895 skin cancers tested; 0.15 % in 589 stomach cancers tested; 0.15 % in 125 biliary tract cancers tested; 0.1 % in 548 urinary tract cancers tested; 0.09 % in 1742 lung cancers tested; 0.08 % in 603 endometrium cancers tested; 0.08 % in 238 bone cancers tested; 0.08 % in 1512 liver cancers tested; 0.07 % in 710 oesophagus cancers tested; 0.06 % in 1463 breast cancers tested; 0.05 % in 1433 kidney cancers tested; 0.04 % in 865 ovary cancers tested; 0.03 % in 881 prostate cancers tested; 0.03 % in 2052 central nervous system cancers tested; 0.03 % in 1445 pancreas cancers tested; 0.02 % in 558 thyroid cancers tested; 0.02 % in 1983 haematopoietic and lymphoid cancers tested.

Most frequent mutations with the number of reports indicated in brackets: R721* (6); T577A (4); R910C (4); .

Only 6 deletions, 6 insertions, and no complex mutations are noted on the COSMIC website.