Somatic loss of ATM is a late event in pancreatic tumorigenesis
Paranal, Raymond M; Jiang, Zhengdong; Hutchings, Danielle; Kryklyva, Valentyna; Gauthier, Christian; Fujikura, Kohei; Nanda, Neha; Huang, Bo; Skaro, Michael; Wolfgang, Christopher L; He, Jin; Klimstra, David S; Brand, Randall E; Singhi, Aatur D; DeMarzo, Angelo; Zheng, Lei; Goggins, Michael; Brosens, Lodewijk Aa; Hruban, Ralph H; Klein, Alison P; Lotan, Tamara; Wood, Laura D; Roberts, Nicholas J
(2023) Journal of Pathology, volume 260, issue 4, pp. 455 - 464
(Article)
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
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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.
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Keywords: ATM, cancer, DNA, immunohistochemistry, inherited, pancreatic, pathogenic, sequencing, somatic, variant, Pathology and Forensic Medicine, Journal Article
ISSN: 0022-3417
Publisher: John Wiley & Sons Inc.
Note: Funding Information: This study was supported by National Institutes of Health/National Cancer Institute P50 CA62924 and R00 CA190889; Susan Wojcicki and Dennis Troper, The Sol Goldman Pancreatic Cancer Research Center; the Rolfe Pancreatic Cancer Foundation; the Joseph C. Monastra Foundation; the Gerald O. Mann Charitable Foundation (Harriet and Allan Wulfstat, Trustees); and the Dutch Cancer Society (Grant 2016‐I 10289). We thank Kevin T. Jamouss for help with slide imaging. Publisher Copyright: © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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