PT - JOURNAL ARTICLE AU - Kohei Fujikura AU - Waki Hosoda AU - Matthäus Felsenstein AU - Qianqian Song AU - Johannes G Reiter AU - Lily Zheng AU - Violeta Beleva Guthrie AU - Natalia Rincon AU - Marco Dal Molin AU - Jonathan Dudley AU - Joshua D Cohen AU - Pei Wang AU - Catherine G Fischer AU - Alicia M Braxton AU - Michaël Noë AU - Martine Jongepier AU - Carlos Fernández-del Castillo AU - Mari Mino-Kenudson AU - C Max Schmidt AU - Michele T Yip-Schneider AU - Rita T Lawlor AU - Roberto Salvia AU - Nicholas J Roberts AU - Elizabeth D Thompson AU - Rachel Karchin AU - Anne Marie Lennon AU - Yuchen Jiao AU - Laura D Wood TI - Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic <em>KLF4</em> mutations predominantly in low-grade regions AID - 10.1136/gutjnl-2020-321217 DP - 2021 May 01 TA - Gut PG - 928--939 VI - 70 IP - 5 4099 - http://gut.bmj.com/content/70/5/928.short 4100 - http://gut.bmj.com/content/70/5/928.full SO - Gut2021 May 01; 70 AB - 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 &gt;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.Data are available from the authors on reasonable request and approval of data sharing by institutional review boards.