Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations

Catherine G. Fischer, Violeta Beleva Guthrie, Alicia M. Braxton, Lily Zheng, Pei Wang, Qianqian Song, James F. Griffin, Peter E. Chianchiano, Waki Hosoda, Noushin Niknafs, Simeon Springer, Marco Dal Molin, David Masica, Robert B Scharpf, Elizabeth Thompson, Jin He, Christopher Wolfgang, Ralph H Hruban, Nicholas Roberts, Anne Marie O'Broin-Lennon & 3 others Yuchen Jiao, Rachel Karchin, Laura Delong Wood

Research output: Contribution to journalArticle

Abstract

Background & Aims: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. Methods: We microdissected neoplastic tissues from 6–24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. Results: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. Conclusions: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1123-1137.e22
JournalGastroenterology
Volume157
Issue number4
DOIs
StatePublished - Oct 1 2019

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Clone Cells
Mutation
Neoplasms
Carcinogenesis
Pancreatic Neoplasms
Exome
Genes

Keywords

  • carcinogenesis
  • driver gene
  • oncogene
  • PDAC

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations. / Fischer, Catherine G.; Beleva Guthrie, Violeta; Braxton, Alicia M.; Zheng, Lily; Wang, Pei; Song, Qianqian; Griffin, James F.; Chianchiano, Peter E.; Hosoda, Waki; Niknafs, Noushin; Springer, Simeon; Dal Molin, Marco; Masica, David; Scharpf, Robert B; Thompson, Elizabeth; He, Jin; Wolfgang, Christopher; Hruban, Ralph H; Roberts, Nicholas; O'Broin-Lennon, Anne Marie; Jiao, Yuchen; Karchin, Rachel; Wood, Laura Delong.

In: Gastroenterology, Vol. 157, No. 4, 01.10.2019, p. 1123-1137.e22.

Research output: Contribution to journalArticle

Fischer, CG, Beleva Guthrie, V, Braxton, AM, Zheng, L, Wang, P, Song, Q, Griffin, JF, Chianchiano, PE, Hosoda, W, Niknafs, N, Springer, S, Dal Molin, M, Masica, D, Scharpf, RB, Thompson, E, He, J, Wolfgang, C, Hruban, RH, Roberts, N, O'Broin-Lennon, AM, Jiao, Y, Karchin, R & Wood, LD 2019, 'Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations', Gastroenterology, vol. 157, no. 4, pp. 1123-1137.e22. https://doi.org/10.1053/j.gastro.2019.06.001
Fischer, Catherine G. ; Beleva Guthrie, Violeta ; Braxton, Alicia M. ; Zheng, Lily ; Wang, Pei ; Song, Qianqian ; Griffin, James F. ; Chianchiano, Peter E. ; Hosoda, Waki ; Niknafs, Noushin ; Springer, Simeon ; Dal Molin, Marco ; Masica, David ; Scharpf, Robert B ; Thompson, Elizabeth ; He, Jin ; Wolfgang, Christopher ; Hruban, Ralph H ; Roberts, Nicholas ; O'Broin-Lennon, Anne Marie ; Jiao, Yuchen ; Karchin, Rachel ; Wood, Laura Delong. / Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations. In: Gastroenterology. 2019 ; Vol. 157, No. 4. pp. 1123-1137.e22.
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AU - Fischer, Catherine G.

AU - Beleva Guthrie, Violeta

AU - Braxton, Alicia M.

AU - Zheng, Lily

AU - Wang, Pei

AU - Song, Qianqian

AU - Griffin, James F.

AU - Chianchiano, Peter E.

AU - Hosoda, Waki

AU - Niknafs, Noushin

AU - Springer, Simeon

AU - Dal Molin, Marco

AU - Masica, David

AU - Scharpf, Robert B

AU - Thompson, Elizabeth

AU - He, Jin

AU - Wolfgang, Christopher

AU - Hruban, Ralph H

AU - Roberts, Nicholas

AU - O'Broin-Lennon, Anne Marie

AU - Jiao, Yuchen

AU - Karchin, Rachel

AU - Wood, Laura Delong

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N2 - Background & Aims: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. Methods: We microdissected neoplastic tissues from 6–24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. Results: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. Conclusions: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.

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