Journal
GUT
Volume 70, Issue 5, Pages 928-939Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2020-321217
Keywords
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Categories
Funding
- NIH/NCI [P50 CA62924]
- NIH/NIDDK [K08 DK107781]
- Sol Goldman Pancreatic Cancer Research Center
- Buffone Family Gastrointestinal Cancer Research Fund
- Carol S. and Robert M. Long Pancreatic Cancer Research Fund
- Kaya Tuncer Career Development Award in Gastrointestinal Cancer Prevention
- AGA-Bernard Lee Schwartz Foundation Research Scholar Award in Pancreatic Cancer
- Sidney Kimmel Foundation for Cancer Research Kimmel Scholar Award
- AACR-IncyteCorporation Career Development Award for Pancreatic Cancer Research
- American Cancer Society Research Scholar Grant [RSG-18-143-01-CSM]
- Emerson Collective Cancer Research Fund
- Rolfe Pancreatic Cancer Foundation
- Joseph C Monastra Foundation
- The Gerald O Mann Charitable Foundation (Allan Wulfstat, Trust)
- Lustgarten Foundation for Pancreatic Cancer Research
- CAMS Innovation Fund for Medical Sciences [2016-I2M-1-001, 2019-I2M-1-001]
- Virginia and D.K. Ludwig Fund for Cancer Research
- Sol Goldman Sequencing Facility at Johns Hopkins
- Howard Hughes Medical Institute
- Associazione Italiana Ricerca Cancro [12182]
- The Gerald O Mann Charitable Foundation (Harriet Trust)
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This study conducted multiregion whole exome sequencing on IPMNs and identified hotspot mutations in KLF4 in both low-grade and high-grade regions. Mutations in KLF4 were more prevalent in low-grade IPMNs, highlighting distinct molecular features and diverse pathways to high-grade dysplasia.
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.
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