Somatic loss ofATMis a late event in pancreatic tumorigenesis

Abstract

AbstractUnderstanding the timing and spectrum of genetic alterations that contribute to the development of pancreatic cancer is essential for effective interventions and treatments. The aim of this study was to characterize somaticATMalterations in noninvasive pancreatic precursor lesions and invasive pancreatic adenocarcinomas from patients with and without pathogenic germlineATMvariants. DNA was isolated and sequenced from the invasive pancreatic ductal adenocarcinomas and precursor lesions of patients with a pathogenic germlineATMvariant. Tumor and precursor lesions from these patients as well as colloid carcinoma from patients without a germlineATMvariant were immunolabeled to assess ATM expression. Among patients with a pathogenic germlineATMvariant, somaticATMalterations, either mutations and/or loss of protein expression, were identified in 75.0% of invasive pancreatic adenocarcinomas but only 7.1% of pancreatic precursor lesions. Loss of ATM expression was also detected in 31.0% of colloid carcinomas from patients unselected for germlineATMstatus, significantly higher than in pancreatic precursor lesions [pancreatic intraepithelial neoplasms (p = 0.0013); intraductal papillary mucinous neoplasms,p = 0.0040] and pancreatic ductal adenocarcinoma (p = 0.0076) unselected for germline ATM status. These data are consistent with the second hit toATMbeing a late event in pancreatic tumorigenesis. © 2023 The Authors.The Journal of Pathologypublished by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.