The Role of Inherited Pathogenic CDKN2A Variants in Susceptibility to Pancreatic Cancer.

ABSTRACT: CDKN2A is cell cycle negative regulator, and the role of CDKN2A in the development of pancreatic ductal adenocarcinoma, which continues to be a lethal cancer, is well-established. Somatic loss of CDKN2A is considered one of the major drivers of pancreatic tumorigenesis. CDKN2A gene is one of the pancreatic cancer susceptibility gene; in addition to melanoma, pathogenic germline CDKN2A variants have been identified in up to 3.3% patients with pancreatic ductal adenocarcinoma depending on family history of disease. Carriers of a known pathogenic germline CDKN2A variant have up to a 12.3-fold increased risk of developing pancreatic cancer. Recently, several studies have demonstrated the benefit of clinical surveillance in patients with pathogenic germline CDKN2A variants. Therefore, identification of patients with a pathogenic germline CDKN2A variant is important for screening of at-risk relatives for pancreatic cancer. It has the potential to lead to the detection of early, potentially curable pancreatic cancer and precursor neoplasms, and reduce mortality. Furthermore, patients with a germline pathogenic CDKN2A variant and somatic loss of CDKN2A may benefit in the future from treatment with targeted therapies, such as a CDK4/6 inhibitor.