Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions.

Autor:	Fujikura K; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Hosoda W; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan., Felsenstein M; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Surgery, Charité Universitätsmedizin, Berlin, Germany., Song Q; State Key Lab of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Reiter JG; Canary Center for Cancer Early Detection in Department of Radiology, Stanford Cancer Institute, and Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, California, USA., Zheng L; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Beleva Guthrie V; Personal Genome Diagnostics, Baltimore, Maryland, USA., Rincon N; Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA., Dal Molin M; Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Dudley J; Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Cohen JD; Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Wang P; State Key Lab of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Fischer CG; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Braxton AM; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Noë M; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Jongepier M; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Fernández-Del Castillo C; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Mino-Kenudson M; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Schmidt CM; Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA., Yip-Schneider MT; Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA., Lawlor RT; ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy., Salvia R; General and Pancreatic Surgery Department, The Pancreas Institute and Hospital Trust of Verona, Verona, Italy., Roberts NJ; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Thompson ED; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Karchin R; Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA., Lennon AM; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Jiao Y; State Key Lab of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China ldwood@jhmi.edu jiaoyuchen@cicams.ac.cn., Wood LD; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA ldwood@jhmi.edu jiaoyuchen@cicams.ac.cn.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2021 May; Vol. 70 (5), pp. 928-939. Date of Electronic Publication: 2020 Oct 07.
DOI:	10.1136/gutjnl-2020-321217
Abstrakt:	Objective: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression. Design: We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples. Results: Our multiregion whole exome sequencing identified KLF4 , a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in KLF4 were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in KLF4 were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs. Conclusion: Hotspot mutations in KLF4 occur at high prevalence in IPMNs. Unique among pancreatic driver genes, KLF4 mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway. Competing Interests: Competing interests: LDW receives research support from Applied Materials. VBG is an employee of Personal Genome Diagnostics. The other authors declare no conflict of interest. (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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