Association of Ataxia Telangiectasia Mutated (ATM) Gene Mutation/Deletion with Rhabdomyosarcoma

Abstract

Rhabdomyosarcoma is a common malignancy in children. There are two major types of rhabdomyosarcomas, the embryonal and the alveolar, differing in cytogenetic and morphologic features. The alveolar type of rhabdomyosarcoma is frequently associated with chromosome translocation t(2; 13) and poor clinical prognosis. Pathogenesis of rhabdomyosarcoma remains obscure, and especially it occurs in the location where skeletal muscle is absent. We report here that there is a high frequency of association of rhabdomyosarcoma with ataxia telangiectasia mutated (ATM) gene mutation/deletion. Totally 17 cases of rhabdomyosarcoma specimens were studied by immunohistochemical or immunofluorescent staining with ATM antibody and revealed that 7 of the 17 cases were negative for ATM expression (41%). Further analyses of rhabdomyosarcoma cell lines with RT-PCR revealed that in Rh30 cells, an alveolar rhabdomyosarcoma cell line, there are three separate deletions/mutations of the ATM mRNA. Western blotting analysis of the Rh30 cellular extract with anti-ATM antibody showed that there is an aberrant form of ATM protein within the Rh30 cells that are smaller than normal control. These results suggest, for the first time, a link of ATM gene deletion/mutation with rhabdomyosarcoma, and since ATM kinase is a crucial regulatory protein in DNA damage repair signaling pathway, and ATM deletion/mutation may contribute to pathogenesis of rhabdomyosarcoma.

Analysis of hypermethylation and expression profiles of APC and ATM genes in patients with oral squamous cell carcinoma

“…Various reports have shown the association of ATM mutation with risk of different human malignancies including breast, prostate, and ovarian cancers, mantle cell lymphoma, and B-cell chronic lymphocytic leukemia. The primary molecular pathway(s) by which ATM gene leads to these alterations are not well known [32]. So far, no study has shown strict involvement of ATM gene methylation with OSCC.…”

The mTOR pathway negatively controls ATM by up-regulating miRNAs

“…The relationship between MYCN overexpression and ATM is not absolute, suggesting that factors other than miR-18a and miR-421 may be involved, such as promoter hypermethylation (42,43). The role of ATM in the initiation or progression of childhood solid tumors has not been studied extensively; however undetectable levels of ATM were reported in 7 of 17 (41%) rhabdomyosarcoma samples (44). Persistent MYCN signaling in paravertebral ganglia cells initiates tumorigenesis by altering the physiologic process of neural crest cell deletion (45), suggesting that mTORC1-mediated up-regulation of MYCN may initiate transformation in other embryonal cancers.…”

Alterations of ATM and CADM1 in chromosomal 11q22.3–23.2 region are associated with the development of invasive cervical carcinoma

“…However, in the CIN/CACX, p-Atm expression resembled to its expression in basal/ parabasal layer of normal cervix. Similarly, nuclear expression of Atm was seen in rhabdomyosarcoma cell lines though its cytoplasmic expression was seen in primary tumors (Zhang et al 2003). The cause of cytoplasmic localization of p-Atm is not known, but may be attributed to its function of phosphorylating its downstream effectors like Chek1, which have a cytoplasmic localization.…”