<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.
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.
Tumor immunogenicity was evaluated after ATM inhibition alone and in combination with radiation by assessing TBK1 and Type I interferon (T1IFN) signaling as well as tumor growth following PD-L1/PD-1 checkpoint inhibition.
ATM is an interesting candidate as a tumor suppressor gene because constitutive inactivation of the gene predisposes ataxia telangiectasia patients to lymphoid malignancies.
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.
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.
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 does seem to act as a classic tumor suppressor gene in T-prolymphocytic leukemia, and LOH at the ATM locus is a common event in some tumor types, suggesting a general role for ATM in cancer.
A common assumption has been that the target for the LOH at 11q23.1 in breast carcinoma is the ATM gene, but the area studied has been too large, the density of markers too low, and the number of tumors studied has been too small to draw any firm conclusions.
A micro-array analysis using biopsies from patients with EBV-positive undifferentiated nasopharyngeal carcinoma (NPC) and from cancer-free controls revealed down-regulation of tumour suppressor genes (TSG) not previously associated with this disease; one such gene was the ataxia telangiectasia mutated (ATM) gene.
A phase II study (Study 39; NCT01063517) designed to investigate the combination olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer did not meet its primary endpoint of progression-free survival; however, an improvement in the secondary endpoint of overall survival was recorded with a greater overall survival benefit noted in patients with ATM-negative tumors.
Abnormal DNA damage response protein expression, defined as loss of any one of NBS1, BRCA1, ATM, and/or abnormal p53 expression, was observed in 258 of 399 evaluable cases (64.7%) and was significantly associated with higher tumor grade, larger tumor size, and ER-negative, and/or PR-negative status.