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.
- pancreatic tumours
- pancreatic pathology
- pancreatic cancer
- molecular genetics
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KF, WH, MF and QS contributed equally.
Correction notice This article has been corrected since it published Online First. Figures have been replaced for clarity.
Contributors KF, WH, MF, QS, YJ and LDW designed the study. WH, MDM, CF-dC, MM-K, CMS, MY-S, RTL, RS, EDT, AML and LDW contributed to sample acquisition. WH, QS, JD, JC, PW acquired data. KF, MF, QS, JR, LZ, VBG, NR analysed data. KF, WH, MF, QS, JR, LZ, VBG, CGF, AB, MN, MJ, NJR, RK, YJ, LDW interpreted data. KF, LDW wrote the manuscript. All authors critically reviewed the manuscript. LDW provided study supervision.
Funding The authors acknowledge the following sources of funding: NIH/NCI P50 CA62924; NIH/NIDDKK08 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 (Harriet and Allan Wulfstat, Trustees); Susan Wojcicki and Denis Troper; Lustgarten Foundation for Pancreatic Cancer Research; CAMS Innovation Fund for Medical Sciences 2016-I2M-1-001 and 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 (grant number: 12182).
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.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Ethics approval This study was approved by Institutional Review Board of The Johns Hopkins Hospital. Patients or the public were not involved in the design, conduct, reporting, or dissemination plans of our research.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available from the authors on reasonable request and approval of data sharing by institutional review boards.
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