ATM Mutations and radio-sensitivity : a review of molecular pathology and cancer susceptibility

Abstract

Hereditary mutations of genes involved in DNA repair have resulted in increased susceptibility to a variety of cancers. Mutations in ataxia telangiectasia mutated (ATM) gene result in an autossomal recessive disorder ataxia telangiectasia syndrome (AT), which manifests with greater predisposition to various types of cancer, radiotherapy resistance and adverse prognosis. Therefore, patients with AT and their cells are radiosensitive, mainly because ATM protein kinase is a regulator of DNA damage identification and cell cycle control in response to ionizing radiation. Blood relatives of AT can also carry a pathogenic ATM mutation, which presents similar or even other risks (not yet completely described), although apparently healthy. Due to the unusual phenotype of radiosensitive cells in ATM patients, it has been the focus of numerous studies in the past two decades. The efficiency of radiotherapy treatment among ATM patients has been questioned due to its toxic effect on normal tissue. As certain ATM signaling provided valuable information about the response to DNA damage and cancer, but the understanding of the role of ATM in radio sensitivity is still incipient and, therefore, the molecular determinants of the clinical response are poorly understood so far. On the face of these considerations, this work presents a review of the normal structure and function of the ATM with compilation of the current literature on the risk of radio sensitivity and malignancy among patients with mutations in the ATM.