ATM is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHEK2 and H2AX are tumor suppressors.
Various types of ATM germline mutations have been described, dispersed throughout the gene, and therefore most patients are compound heterozygotes; most mutations appear to inactivate the ATM protein by truncation, large deletions, or annulation of initiation or termination, although “missense” mutations have been described in the PI3 kinase domain and the leucine zipper motif. Missense mutations outside of the PI3 kinase and leucine zipper domains have been described among breast cancer patients, although these mutations have not been found in A-T patients. Whether these mutations contribute to breast cancer though not to ataxia-telangiectasia remains controversial.
Defects in ATM are the cause of ataxia telangiectasia (AT). This rare recessive disorder is characterized by progressive cerebellar ataxia, dilation of the blood vessels in the conjunctiva and eyeballs, immunodeficiency, growth retardation and sexual immaturity. AT patients have a strong predisposition to cancer; about 30% of patients develop tumors, particularly lymphomas and leukemias. AT patients have an increased risk for breast cancer that has been ascribed to ATM's interaction and phosphorylation of BRCA1 and its associated proteins following DNA damage. Cells from affected individuals are highly sensitive to damage by ionizing radiation and resistant to inhibition of DNA synthesis following irradiation. The phenotypic manifestation of AT is due to the broad range of substrates for the ATM kinase, involving DNA repair, apoptosis, G1/S, intra-S checkpoint and G2/M checkpoints, gene regulation, translation initiation, and telomere maintenance. Therefore a defect in ATM has severe consequences in repairing certain types of damage to DNA, and cancer may result from improper repair.
Somatic mutations have been observed in cancers of haematopoietic and lymphoid tissue (T-acute lymphoblastic leukemia, T-cell prolymphocytic leukemia, B-cell non-Hodgkin's lymphoma, B-cell chronic lymphocytic leukemia), ovary, lung, large intestine, stomach and upper aerodigestive tract. Biallelic mutation can occur in T-prolymphocytic leukaemia. Most mutations are substitutions. No mutation hot spot has been described (mutations are dispersed throughout the gene).
References (open access):
Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls. Fletcher O, Johnson N, dos Santos Silva I, Orr N, Ashworth A, Nevanlinna H, Heikkinen T, Aittomäki K, Blomqvist C, Burwinkel B, Bartram CR, Meindl A, Schmutzler RK, Cox A, Brock I, Elliott G, Reed MW, Southey MC, Smith L, Spurdle AB, Hopper JL, Couch FJ, Olson JE, Wang X, Fredericksen Z, Schürmann P, Waltes R, Bremer M, Dörk T, Devilee P, van Asperen CJ, Tollenaar RA, Seynaeve C, Hall P, Czene K, Humphreys K, Liu J, Ahmed S, Dunning AM, Maranian M, Pharoah PD, Chenevix-Trench G; kConFab Investigators; AOCS Group, Beesley J, Bogdanova NV, Antonenkova NN, Zalutsky IV, Anton-Culver H, Ziogas A, Brauch H, Ko YD, Hamann U; GENICA Consortium, Fasching PA, Strick R, Ekici AB, Beckmann MW, Giles GG, Severi G, Baglietto L, English DR, Milne RL, Benítez J, Arias JI, Pita G, Nordestgaard BG, Bojesen SE, Flyger H, Kang D, Yoo KY, Noh DY, Mannermaa A, Kataja V, Kosma VM, García-Closas M, Chanock S, Lissowska J, Brinton LA, Chang-Claude J, Wang-Gohrke S, Broeks A, Schmidt MK, van Leeuwen FE, Van't Veer LJ, Margolin S, Lindblom A, Humphreys MK, Morrison J, Platte R, Easton DF, Peto J; Breast Cancer Association Consortium. Cancer Epidemiol Biomarkers Prev. 2010 Sep;19(9):2143-51.