Several single-nucleotide polymorphisms (SNPs) have been described in the ATM gene; however, their association with cancer risk or radiosensitivity remains to be fully established.
These findings indicate that epigenetic silencing of ATM expression occurs in locally advanced breast tumors, and establish a link at the molecular level between reduced ATM function and sporadic breast malignancy.
A-T patients exhibit a predisposition to the development of a wide range of lymphoid tumours, suggesting that the ATM protein normally plays an important role in the prevention of both T and B cell malignancies.
BRCA1 and BRCA2 are the major genes for high-penetrance familial breast and ovarian cancer, whereas mutations in ATM or Chek2 confer more modest cancer risk.
Recessive mutations in the cancer gene Ataxia Telangiectasia Mutated (ATM), at a locus previously associated with metformin response, cause dysglycaemia and insulin resistance.
High ATM expression helps DNA repair mechanisms to maintain the cells in the OPMD stage, but low ATM expression causes DNA damage accumulation to increase cell malignancy.
Experimental evidence supporting the Damage Surveillance Network model is summarized, followed by a discussion of how defects in the ATM-dependent signal transduction network might account for the A-T phenotype and what insights this new understanding of A-T can offer regarding DNA damage response networks, genomic instability, and cancer.
While these translocations target and activate the TCL1 oncogene at 14q32 to cause T cell pro-lymphocytic leukemia (T-PLL), the TCRα/δ;14q32 translocations in ATM-deficient T cell acute lymphoblastic leukemia (T-ALL) have not been characterized and their role in cancer pathogenesis remains unknown.
Cancer-specific survival was significantly reduced in patients whose tumors exhibited LOH of markers D11S2179 (within the ATM gene), D11S1778, D11S1294, and D11S1818.
Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB) that might inhibit cancer cell proliferation, but the mechanisms through which telmisartan affects various cancers remain unknown.
Analyses of ATM mutations in A-T patients and in sporadic tumors suggest the existence of two classes of ATM mutation: null mutations that lead to A-T and dominant negative missense mutations that may predispose to cancer in the heterozygous state.
Biallelic mutations in ATM result in the neurodegenerative syndrome Ataxia-Telangiectasia, while ATM haploinsufficiency increases the risk of cancer and other diseases.
The radiosensitivity gene ATDC and the genes encoding the DNA-binding protein inhibitor ID1 and the phospholipase inhibitor uteroglobin were significantly down-regulated in the cancer samples.
In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014).
Ataxia-telangiectasia (A-T), an autosomal recessive disorder characterized by progressive neurologic dysfunction, oculocutaneous telangiectasia, immunodeficiency, and cancer susceptibility, is caused by mutations in the ATM gene.
Further SNPs associated with CRC risk included several previously reported to be associated with cancer risk including ATMF858L [OR=1.48; 95% confidence interval (CI): 1.06-2.07] and P1054R (OR=1.42; 95% CI: 1.14-1.77) and MTHFR A222V (OR=0.82; 95% CI: 0.69-0.97).
Furthermore, rs9257445 (ZNF311) was associated with TL in HetAT subjects and rs6060627 (BCL2L1) modified cancer risk in HetAT and non-HetAT women.Our findings suggest that carriage of an ATM mutation impacts on the age-related TL shortening and that TL per se is not related to cancer risk in ATM carriers.
Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer.