In addition, they mirror the sensitivity of ATM tumor suppressor function and unveil a new mechanism by which ATM might prevent human breast tumorigenesis, namely a direct inhibitory effect on the basal proliferation of normal mammary epithelial cells.
Overexpression of the N-Myc transcription factor, an oncogene frequently amplified in neuroblastoma, induced miR-421 expression, which, in turn, down-regulated ATM expression, establishing a linear signaling pathway that may contribute to N-Myc-induced tumorigenesis in neuroblastoma.
This study suggests support to the literature that ATM polymorphisms and environmental tobacco smoke exposure have a role in lung carcinogenesis among never smokers.
These findings suggest that Fhit plays a key role in the regulation of the ataxia telangiectasia mutated-Chk2 DNA damage response during oral carcinogenesis.
We discuss this novel association, the general risk of neoplasic complications in these patients, the natural history of thyroid carcinoma in the pediatric population and the potential link between thyroid carcinogenesis and ataxia-telangiectasia mutated gene (ATM) mutation.
Analysis of the dynamic engagement of DDR along the different stages of lung tumorigenesis showed that 53BP1 loss occurs early at the transition from normal to dysplastic change whereas the activated forms of ATM and CHK2, but not gamma-H2AX, initially accumulate in pre-invasive lesions and are then lost during tumor progression.
Due to the role of ATM and NBS in tumor suppression and the response to chemotherapy and radiotherapy, these findings may assist in the development of a more rational approach to cancer treatment, as well as a better understanding of tumorigenesis.
To investigate the potential role of somatic ATM mutations in the tumorigenesis of breast cancer, the ATM gene was scanned in 58 mammary carcinomas using DOVAM-S (detection of virtually all mutations-SSCP [single-strand conformation polymorphism]), a robotically enhanced, highly redundant form of SSCP that detects virtually all mutations.
It is concluded that ATM is likely to play an important role at the pregerminal center stage and a model is proposed where loss of ATM function during B-cell ontogeny drives B-CLL tumorigenesis in pregerminal B cells by a dual defect in p53 damage response and repair of chromosome breaks.
The primary focus of this international, multidisciplinary, National Cancer Institute-sponsored workshop was to discuss ongoing and planned epidemiologic studies aimed at understanding the complexities of the ATM gene and its role in carcinogenesis.
These data suggest that 11q deletions and dysfunction of the ATM gene might have significance in the tumorigenesis of certain subsets of hematological malignancies.
Moreover, we discuss how tumor suppressor proteins such as p53, ATM, Brca1 and Brca2 have been linked to such pathways, and how accumulating evidence is connecting deficiencies in cellular responses to DNA DSBs with tumorigenesis.
Support for our hypothesis comes from the observations that: (a) the extent of DSB-initiated CIN in tumors significantly increased as tumors progressed to poorer grades or later stages; (b) in the sequential steps toward CIN, the loci of p53 and ATM, the key checkpoint genes against DSB, were lost at the earliest stage; and (c) many loci identified to be important in breast tumorigenesis were the genomic sites possibly harboring the genes involved in DSB-related checkpoint/repair (including RAD51, RAD52, and BRCA1) or CIN (including FA-A, FA-D, and WRN), and a higher number of these loci showing LOH was significantly associated with increased level of DSB-initiated CIN (P < 0.0001).
Studies with A-T mouse models have helped determine the basis of lymphoid tumorigenesis in A-T and have shown that ATM plays a critical role in maintaining genetic stability by ensuring high-fidelity execution of chromosomal events.
This high rate of somatic inactivation of ATM may indicate either that these rare variants play a role in breast cancer development or alternatively that a neighboring tumor suppressor gene is important for tumorigenesis.