ATM and pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC)

• the utilization of genomic sequencing has identified therapeutically relevant alterations in about 25% of PDAC patients, most notably in the DNA damage response (DDR) genes rendering cancer cells more sensitive to DNA damaging agents, and DNA damage response inhibitors, such as PARP inhibitors
  
  
• ATM is one of the most commonly mutated DDR genes, with somatic mutations identified in 2 -18% of PDACs and germline mutations identified in 1-34% of patients with PDAC
  • ATM plays a complex role as a cell cycle checkpoint kinase, regulator of a wide array of downstream proteins, and responder to DNA damage for genome stability
  • ATM is a breast cancer susceptibility gene that coordinates the DNA double-strand breaks repair
    • deleterious mutations of ATM gene were first reported by Roberts and his colleagues in two FPC families with at least three members affected by pancreatic cancer (2)
  • disruption of ATM signaling leads to downstream reliance on ATR and CHK1 among other DNA repair mechanisms, which may enable exploiting the inhibition of downstream proteins as therapeutic targets in ATM-mutated PDACs
• surveillance for familial pancreatic cancer if germiline ATM mutation carriers (3)
  • experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55
  • germline ATM mutation carriers with one affected first-degree relative are now considered eligible for surveillance
  • experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities

Reference:

1. Armstrong SA, Schultz CW, Azimi-Sadjadi A, Brody JR, Pishvaian MJ. ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications. Mol Cancer Ther. 2019;18(11):1899-1908. doi:10.1158/1535-7163.MCT-19-0208
2. Roberts NJ, Jiao Y, Yu J, Kopelovich L, Petersen GM, Bondy ML, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012 Jan;2(1):41-6
3. Goggins M et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut 2020, 69 (1): 7-17