Cancer, brain disorders

Ataxia Telangiectasia (AT); Ataxia; Nijmegen breakage syndrome; Idiopathic acute transverse myelitis; Cervical dystonia; Telangiectasis; Asphyxiating thoracic dystrophy; Nijmegen breakage syndrome-like disorder; Chromosome 11q Deletion; Ataxia-Telangiectasia variant; Combined Cervical Dystonia;

Loss of function mutations in ATM are responsible for ataxia telangiectasia (AT) and immune deficiency. AT is a rare recessive disorder characterized by progressive loss of motor control (from cerebellar ataxia), and dilation of superficial blood vessels in the conjunctiva and eyeballs. About 30% of ATM patients have a strong predisposition to cancer, particularly lymphomas and leukemias. Cells from AT cancer patients are very sensitive to damage by ionizing radiation and following irradiation are resistant to inhibition of DNA synthesis. Many different mutations in AT cancer patients are observed, which is consistent with loss of function mutations that underlie the development of cancer.
 

Breast cancer; mantle cell lymphoma (MCL); chronic lymphocytic leukemia (CLL); B-cell chronic lymphocytic leukemia (B-CLL); bilateral breast cancer; prolymphocytic leukemia (PLL); ovarian cancer; T-cell prolymphocytic leukemia (T-CLL); familial chronic lymphocytic leukemia; breast cancer, somatic; lymphoma, B-cell non-Hodgkin, somatic; T-cell prolymphocytic leukemia, somatic;

ATM appears to be a tumour suppressor protein (TSP). Cancer-related mutations in human tumours point to a loss of function of the protein kinase. The active form of the protein kinase normally acts to inhibit tumour cell proliferation. Approximately 30% of cancers, mostly lymphomas and leukemias, arise due to defects in DNA damage repair. ATM mutations are also associated with melanoma, breast, lymphoid tissue, lung, ovarian, stomach, and upper aerodigestive tract tumours. In human tumours, a wide range of point mutations, complex mutations, deletions and insertions are distributed through out the protein, which is characteristic for a tumour suppressor protein.
 

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= +48, p<0.051); Brain glioblastomas (%CFC= -59, p<0.043); Brain oligodendrogliomas (%CFC= -72, p<0.023); Cervical cancer stage 2B (%CFC= -59, p<0.051); Classical Hodgkin lymphomas (%CFC= -47, p<0.015); Clear cell renal cell carcinomas (cRCC) (%CFC= +50, p<0.066); Colorectal adenocarcinomas (early onset) (%CFC= +69, p<0.013); and T-cell prolymphocytic leukemia (%CFC= -48, p<0.0001). The COSMIC website notes an up-regulated expression score for ATM in diverse human cancers of 279, which is 0.6-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 67 for this protein kinase in human cancers was 1.1-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: 0.14 % in 30040 diverse cancer specimens. This rate is 1.85-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: 0.64 % in 1284 large intestine cancers tested; 0.31 % in 4073 haematopoietic and lymphoid cancers tested; 0.24 % in 859 skin cancers tested; 0.2 % in 619 stomach cancers tested; 0.19 % in 603 endometrium cancers tested; 0.18 % in 500 urinary tract cancers tested; 0.15 % in 2143 lung cancers tested; 0.1 % in 984 upper aerodigestive tract cancers tested; 0.1 % in 1284 liver cancers tested; 0.09 % in 817 prostate cancers tested; 0.09 % in 1333 pancreas cancers tested; 0.08 % in 607 oesophagus cancers tested; 0.07 % in 2139 breast cancers tested; 0.07 % in 1711 kidney cancers tested.

Most frequent mutations with the number of reports indicated in brackets: N1983S (23); R337C (19); R337H (12); D1853N (13).

Broad distribution of mutation sites with point mutations, complex mutations, insertions and deletions over entire protein length. This is characteristic for a tumour suppressor protein.