1. Volume 156, Issue 3, Pages 647-661.e2 (February 2019)
Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features 
Yuko Omori, Yusuke Ono, Mishie Tanino, Hidenori Karasaki, Hiroshi Yamaguchi, Toru Furukawa, Katsuro Enomoto, Jun Ueda, Atsuko Sumi, Jin Katayama, Miho Muraki, Kenzui Taniue, Kuniyuki Takahashi, Yoshiyasu Ambo, Toshiya Shinohara, Hiroshi Nishihara, Junpei Sasajima, Hiroyuki Maguchi, Yusuke Mizukami, Toshikatsu Okumura, Shinya Tanaka 
Gastroenterology 
Volume 156, Issue 3, Pages e2 (February 2019)
DOI: /j.gastro
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2. Gastroenterology 2019 156, 647-661. e2DOI: (10. 1053/j. gastro. 2018
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3. Figure 1
Tracing the molecular signature and tumor geography between coexisting IPMNs and related PDAs. (A) Thirty-three IPMN-related PDAs were classified into IPMN-derived PDAs and concomitant PDAs by morphologic assessment. Based on the concordance of the molecular signatures between the coexisting IPMNs and invasive cancers, the mode of tumor evolution was categorized into the following molecular subtypes (see details in Supplementary Figures 3 and 4): sequential (succeeding the IPMN signature, originated from/with IPMN), branch-off (diverging from founder lesion, showing identical KRAS mutation to IPMN), and de novo (carcinogenesis from the founder clone independent of the coexisting IPMN). The concordance of the KRAS mutation profiles of coexisting IPMN and invasive carcinoma is shown at the bottom. (B) The box-and-whisker plot shows the distance from invasive cancer to a coexisting IPMN depending on KRAS profile in the concomitant PDAs. The whiskers indicate the 10th and 90th percentiles. The middle bar denotes the median (P = .0397, Mann–Whitney U test). (C) Concordance of mutations and immunohistochemical profile between the coexisting IPMN and related PDA. Molecular signatures marked by mutations in 18 PDA/IPMN-related genes are shown for each coexisting IPMN-related PDA pair (top panel). For TP53, SMAD4, CDKN2A/p16, RNF43, and CTNNB1, the protein expression pattern by immunohistochemistry were also grouped (bottom panel). Sharp, metachronous secondary invasive cancer.
Gastroenterology  , e2DOI: ( /j.gastro )
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4. Figure 2
Representative cases of each molecular subtype. (A) Sequential subtype (case 30). The histogram shows sequential changes in the frequencies for mutant KRAS and GNAS alleles during the neoplastic progression from the coexisting IPMN with LG dysplasia (LG IPMN) through increasing grades of dysplasia (HG IPMN) to invasive carcinoma (INV). (B) De novo subtype (case 17). (C) Branch-off subtype (case 18) with a contiguous neoplastic lesion between the IPMN and cancer via the Santorini duct and the Wirsung duct. Details of molecular tracing, including data on tumor morphology and locations of each case enrolled in the current study, are shown in Supplementary Figure 4. For case 18, the multiregional profile of somatic mutations and DNA methylation alterations were visualized as heat maps. (Only recurrent mutations are shown.) Phylogenetic trees represent the similarity among the multiple tumor compartments. Letters in black and gray indicate pathogenic mutation and variant of unknown significance, respectively. VAF; variant allele frequency.
Gastroenterology  , e2DOI: ( /j.gastro )
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5. Figure 3
Clinical outcome of the revised molecular subtypes of IPMN-related PDA. Kaplan–Meier analysis shows the relationship of the molecular subtypes to disease-free survival and overall survival. CI, confidence interval; HR, hazard ratio.
Gastroenterology  , e2DOI: ( /j.gastro )
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6. Figure 4
Variations in KRAS and GNAS mutations among microscopic neoplastic lesions in the grossly normal pancreata of the resected specimens of IPMN-related cancers. (A) Significantly larger numbers of MNLs in the pancreata of the branch-off and de novo subtypes were found relative to the sequential subtype of PDAs. ∗P < .05 vs sequential subtype. (B) The frequency of KRAS and GNAS mutations in MNLs is shown. ∗P < .05. (C) KRAS variants among invasive cancers, IPMNs, and MNLs represent greater diversity in the branch-off and de novo subtypes relative to the sequential group. ∗∗P < (D) Variations in KRAS and GNAS mutations in invasive cancers (black boxes), IPMNs (black circles), and MNLs (white circles). The diversity of the mutations in multicentric IPMNs and MNLs is shown. (E) The distribution of the tumor suppressor gene mutation in MNLs, along with the KRAS and GNAS mutations, is shown. NS, not significant.
Gastroenterology  , e2DOI: ( /j.gastro )
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7. Figure 5
Aberrant molecular signatures aggregated into core PDA/IPMN modules. (A) Bar graphs showing 4 core modules commonly deregulated in PDAs/IPMNs with the KRAS mutation, aberrant TP53, CDKN2A/p16, TGF-β pathway, and Wnt signaling defects (CTNNB1 and RNF43) (left panel). The stacked bar graph represents the total number of the 4 core modules and numbers of cases with each molecular subtype (right panel). (B) The proposed model of progression paths during IPMN-related carcinogenesis. In addition to the previously described model of IPMN progression to PDA, direct progression from the IPMN per se (sequential) and independent development of a distinct founder clone from the coexisting IPMN (de novo), we offer a unique subset, branch-off, in which both the coexisting IPMN and invasive lesion may arise from common founders showing identical KRAS mutations. The white circles, triangles, and squares denote the diversity of precursors, including PanIN and incipient IPMN, with a distinct set of driver mutations (KRAS and GNAS). Note: the temporal order of KRAS and GNAS mutations in IPMN has not been defined. The gray and black stars indicate the coexisting IPMN and invasive carcinomas, respectively. The size of each lesion represents the histologic grade of the tumors.
Gastroenterology  , e2DOI: ( /j.gastro )
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