Germline Variants in DNA Damage Repair Genes: An Emerging Role in the Era of Precision Medicine in Pancreatic Adenocarcinoma

• Published in: Annals of gastroenterological surgery Vol. 6; no. 1; pp. 7 - 16
• Main Authors: Shoucair, Sami, Baker, Andrew R., Yu, Jun
• Format: Journal Article
• Language: English
• Published: Japan John Wiley & Sons, Inc 01.01.2022; John Wiley and Sons Inc; Wiley
• Subjects: Cancer therapies; Cell cycle; Chemotherapy; DDR genes; DNA damage; DNA repair; germline variants; Kinases; Mutation; Pancreatic cancer; Precision medicine; Proteins; Review; Surgery; Austria; Europe; Germany; precision medicine; DDR genes; pancreatic cancer; germline variants
• ISSN: 2475-0328; 2475-0328
• DOI: 10.1002/ags3.12514

Pancreatic adenocarcinoma is a lethal disease that is projected to become the second most common cause of cancer deaths by 2030. The role of adjuvant therapy after surgical resection has been established by several clinical trials to prolong survival and improve outcomes. Multiagent chemotherapy seems to be the most promising approach to counteract early recurrence and improve survival; however, in the era of precision medicine, patient selection and individualized therapy seems to hold the key to desirable superior outcomes. Several cancer susceptibility genes have been proven to be associated with an increased risk of pancreatic cancer, both familial and sporadic cases. The role of genomic profiling for germline variants has been extensive and of limited clinical value, considering their low prevalence in pancreatic ductal adenocarcinoma (PDAC). However, an accumulating body of evidence from several studies in the past decade have successfully shown a recognizable value of germline variants in risk assessment and patient stratification. Recently, anti‐PD‐1 therapy (pembrolizumab) has been FDA‐approved for use in solid malignancies with a Mismatch repair deficiency or high Microsatellite instability. Several trials have evaluated the role of poly (ADP‐ribose) polymerase (PARP) inhibitors in patients harboring germline BRCA1/2 mutations. Finally, germline variants in DNA damage response genes and particularly deleterious ones have the potential to guide therapy after surgical resection and serve as biomarkers to predict survival. The dire need to address challenges for applying precision medicine in real‐life clinical settings for PDAC patients lies in further characterizing the genetic and molecular processes through translational research. The role of genomic profiling for germline variants has been extensive and of limited clinical value, considering their low prevalence in pancreatic ductal adenocarcinoma. However, an accumulating body of evidence from several studies in the past decade that have successfully shown a recognizable value of germline variants in risk assessment and patient stratification. Germline variants in DNA damage response genes and particularly deleterious ones have the potential to guide therapy after surgical resection and serve as biomarkers to predict survival.