Somatic loss of ATM is a late event in pancreatic tumorigenesis Journal Article


Authors: Paranal, R. M.; Jiang, Z.; Hutchings, D.; Kryklyva, V.; Gauthier, C.; Fujikura, K.; Nanda, N.; Huang, B.; Skaro, M.; Wolfgang, C. L.; He, J.; Klimstra, D. S.; Brand, R. E.; Singhi, A. D.; DeMarzo, A.; Zheng, L.; Goggins, M.; Brosens, L. A. A.; Hruban, R. H.; Klein, A. P.; Lotan, T.; Wood, L. D.; Roberts, N. J.
Article Title: Somatic loss of ATM is a late event in pancreatic tumorigenesis
Abstract: Understanding 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 somatic ATM alterations in noninvasive pancreatic precursor lesions and invasive pancreatic adenocarcinomas from patients with and without pathogenic germline ATM variants. DNA was isolated and sequenced from the invasive pancreatic ductal adenocarcinomas and precursor lesions of patients with a pathogenic germline ATM variant. Tumor and precursor lesions from these patients as well as colloid carcinoma from patients without a germline ATM variant were immunolabeled to assess ATM expression. Among patients with a pathogenic germline ATM variant, somatic ATM alterations, 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 germline ATM status, 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 to ATM being a late event in pancreatic tumorigenesis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Keywords: immunohistochemistry; adult; clinical article; controlled study; human tissue; protein expression; aged; gene sequence; human cell; genetics; cancer patient; pancreas cancer; pancreatic neoplasms; polymerase chain reaction; adenocarcinoma; metabolism; cancer susceptibility; gene expression; prevalence; intraductal papillary mucinous tumor; adenocarcinoma, mucinous; carcinoma, pancreatic ductal; pathology; carcinogenesis; cell transformation, neoplastic; pancreas carcinoma; dna; genetic susceptibility; pancreas tumor; atm protein; pancreas adenocarcinoma; dna sequence; colloid carcinoma; pancreatic; sequencing; atm; somatic; variant; pancreatic ductal carcinoma; intraepithelial neoplasia; germline mutation; pathogenic; pancreatic carcinoma; inherited; cancer; humans; human; male; female; article; ataxia telangiectasia mutated proteins; atm protein, human; neoplastic cell transformation; invasive ductal carcinoma of the pancreas
Journal Title: Journal of Pathology
Volume: 260
Issue: 4
ISSN: 0022-3417
Publisher: Wiley Blackwell  
Date Published: 2023-08-01
Start Page: 455
End Page: 464
Language: English
DOI: 10.1002/path.6136
PUBMED: 37345735
PROVIDER: scopus
PMCID: PMC10524278
DOI/URL:
Notes: Article -- Source: Scopus
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  1. David S Klimstra
    978 Klimstra