As mutations of the Ataxia Telangiectasia (A-T) gene, ATM, are frequent in T-PLL and as ATM seems to act as a tumour suppressor through a mechanism involving V(D)J recombination, we examined V(D)J recombination in T-PLL.
The DDR signaling as evaluated by phospho-epitope-specific antibodies against Ser139-phosphorylated H2A histone family member X (γH2AX), ataxia telangiectasia mutated (ATM), and ATM- and Rad3-related (ATR) was commonly activated in tumors with both moderate and high extent of accumulated genomic aberrations, the latter tumors showing a more frequent loss of ATM expression.
Instead, the mutation patterns of the tumour suppressor TP53 (which encodes p53), ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage.
Because p53 is commonly inactivated in epithelial malignancies, this suggests that small molecule inhibitors of ATM might selectively sensitize the majority of tumors to the lethal effects of ionizing radiation while sparing normal tissues.
Despite that ataxia-telangiectasia mutated (ATM) is involved in IL-6 promoted lung cancer chemotherapeutic resistance and metastasis, the exact role of ATM in tumor necrosis factor-alpha (TNF-α) increasing tumor migration is still elusive.
With the PGM, all conventional detected mutations were confirmed, and an additional variant of unknown significance in ATM was detected in one of the tumors.
<i>Atm</i>-mutant rats (<i>Atm<sup>L2262P/L2262P</sup></i> ) expressed low levels of ATM protein, suggesting a destabilizing effect of the mutation, and had a significantly reduced lifespan compared with <i>Atm<sup>+/+</sup></i> Whereas these rats did not show cerebellar atrophy, they succumbed to hind-limb paralysis (45%), and the remainder developed tumors.
It is now recognized that mutations in some tumor suppressor genes, such as p53, BRCA1, BRCA2, PTEN, or ATM, or epigenetic functional inactivation of other tumor suppressor genes, such as SYK and NES1, appear to play important early roles in the formation of some breast cancers.
ATM copy number loss was detected in 12% of tumours and associated with lower mRNA levels. miR-421 over-expression was detected in 36.5% of cases which exhibit lower ATM transcript levels (P = 0.075, r = -0.249).
ATM expression levels were measured within the tumor as a whole (tATM) as indicated by pan-cytokeratin expression, tumor nuclear compartment (nATM) as indicated by both DAPI and pan-cytokeratin-positive results, and cancer-associated stroma (csATM) as indicated by vimentin-positive and pan-cytokeratin-negative results.
Intriguingly, recent studies have strongly implicated ATM in the pathogenesis of T-PLL as a tumor suppressor gene, because biallelic inactivation of ATM is frequently observed in this disease; however, translocations involving 11q23 have rarely been reported in T-PLL.
Tumors with ATM mutations only partially correlated with tumors with loss of an ATM allele through an 11q deletion and, interestingly, those 11q-deleted tumors with a second wild-type ATM allele had a preserved DNA damage response.
SETD2-mutated LUADs exhibited relatively poor recurrence- free survival (RFS) and mutations in STK11 and ATM were associated with poor RFS among KRAS-mutant tumors.
ATM is a kinase activated by autophosphorylation upon DNA doublestrand breaks arising from errors during replication, byproducts of metabolism, chemotherapy or ionizing radiations; TP53 is one of the most popular tumor suppressor, with a preeminent role in DNA damage response and repair.
ATM gene expression levels were evaluated in tumor and adjacent normal tissue from patients diagnosed with primary breast cancer or BBD using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) assays.
PDMP + radiotherapy treatment was most effective in inhibiting tumor growth, prolonging survival time, decreasing expression of CD31, CD133, and aldehyde dehydrogenase 1 (ALDH1), inducing G2/M phase arrest, apoptosis, and expression of Ataxia telangiectasia mutated (ATM) and histone H2AX phosphorylation (γ-H2AX).
The ATM gene was shown to sustain frequent loss-of-function mutations in T-PLL tumor cells, consistent with functioning as a tumor suppressor gene in this leukemia.
These results could, at least in part, contribute to the discussion about the possible effects of ACE inhibitors and AT1 receptor antagonists in malignancy, and offer new clues to support their use for tumor control.