Browsing by Subject "Cyst fluid"

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    Multi-region Whole Exome Sequencing of Intraductal Papillary Mucinous Neoplasms Reveals Frequent Somatic KLF4 Mutations Predominantly in Low-Grade Regions
    (BMJ, 2021) Fujikura, Kohei; Hosoda, Waki; Felsenstein, Matthäus; Song, Qianqian; Reiter, Johannes G.; Zheng, Lily; Guthrie, Violeta Beleva; Rincon, Natalia; Molin, Marco Dal; Dudley, Jonathan; Cohen, Joshua D.; Wang, Pei; Fischer, Catherine G.; Braxton, Alicia M.; Noë, Michaël; Jongepier, Martine; Castillo, Carlos Fernández-del; Mino-Kenudson, Mari; Schmidt, C. Max; Yip-Schneider, Michele T.; Lawlor, Rita T.; Salvia, Roberto; Roberts, Nicholas J.; Thompson, Elizabeth D.; Karchin, Rachel; Lennon, Anne Marie; Jiao, Yuchen; Wood, Laura D.; Surgery, School of Medicine
    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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    Serial EUS-Guided FNA for the Surveillance of Pancreatic Cysts: A Study of Long-Term Performance of Tumor Markers
    (Springer, 2022) Rahal, Mahmoud A.; DeWitt, John M.; Patel, Harsh; Schmidt, C. Max; Ceppa, Eugene P.; Simpson, Rachel E.; Sherman, Stuart; Al-Haddad, Mohammad; Medicine, School of Medicine
    Background and aim: The natural history of KRAS mutations in mucinous pancreatic cysts (MPCs) over time remains to be fully understood. The aim of this study was to examine the performance of DNA markers and assess changes of KRAS mutations over time. Methods: Patients who underwent EUS-FNA of pancreatic cysts with at least two separate molecular analysis results were included in the study. We assessed the baseline patient and cyst characteristics, and DNA fluid analysis. The presence of either a KRAS mutation, or a CEA > 192 ng/ml was used as the diagnostic standard for mucinous cysts when surgical pathology was not available. Results: A total of 933 pancreatic cyst fluid samples were collected, including 117 with ≥ 2 FNAs. Examinations were performed over a median of 30 months (range 1-115 months). Forty-three (36%) had a mutant KRAS on the index analysis out of which 26 had a change in their KRAS status to the wild-type. Eighty-one (64%) had a wild-type KRAS on the index analysis out of which 18 had change in their KRAS status to mutant type. There was no significant difference in the index cyst characteristics, presence of symptoms, or main duct involvement based on KRAS status change. Increasing age was associated with a changing KRAS mutation status (p = 0.023). Conclusion: KRAS mutations gain and loss in pancreatic cyst fluid appears to occur frequently during long-term surveillance of MPCs. Age appears to be the only predictor for KRAS change over time.