ATM Serine/Threonine Kinase and its Role in Pancreatic Risk

Abstract

Next-generation sequencing has led to the recent discovery of several novel pancreatic cancer susceptibility genes. These genes include ataxia telangiectasia mutated (ATM), a serine/threonine kinase that is an integral component of DNA repair. Pathogenic germline ATM variants are frequently identified in patients with pancreatic ductal adenocarcinoma (PDAC) with and without a family history of the disease. Loss of ATM is also a frequent somatic event in the development of PDAC. These discoveries have advanced our understanding of the genetic basis of pancreatic cancer risk and will impact patient care through appropriate patient-risk stratification; personalized screening and early detection efforts; and, for some, targeted therapy.

Keywords: ATM; genetics; pancreatic cancer; pancreatic ductal adenocarcinoma; predisposition.

Figure 1

Structure and functions of ATM kinase. Schematic representation of ATM structure and cellular responses to DNA damage. N = n-terminus, C = c-terminus, SBS = substrate binding site, FAT = FAT domain, KINASE = kinase domain, and FATC = FATC domain. DNA damage induces autophosphorylation via MRN. Cellular responses to ATM activation include DNA repair, apoptosis, cell cycle arrest, cell survival, and cell death mediated through various downstream targets.