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 OkumuraShinya Tanaka

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background & Aims: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about the mechanism of progression. This makes it challenging to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses. Methods: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs, and 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors. Results: We determined the clonal relatedness of lesions, based on driver mutations shared by PDAs and concurrent IPMNs, and classified the lesions into 3 subtypes. Twelve PDAs contained driver mutations shared by all concurrent IPMNs, which we called the sequential subtype. This subset was characterized by less diversity in incipient foci with frequent GNAS mutations. Eleven PDAs contained some driver mutations that were shared with concurrent IPMNs, which we called the branch-off subtype. In this subtype, PDAs and IPMNs had identical KRAS mutations but different GNAS mutations, although the lesions were adjacent. Whole-exome sequencing and methylation analysis of these lesions indicated clonal origin with later divergence. Ten PDAs had driver mutations not found in concurrent IPMNs, called the de novo subtype. Expression profiles of TP53 and SMAD4 increased our ability to differentiate these subtypes compared with sequencing data alone. The branch-off and de novo subtypes had substantial heterogeneity among early clones, such as differences in KRAS mutations. Patients with PDAs of the branch-off subtype had a longer times of disease-free survival than patients with PDAs of the de novo or the sequential subtypes. Conclusions: Detailed histologic and genetic analysis of PDAs and concurrent IPMNs identified 3 different pathways by which IPMNs progress to PDAs—we call these the sequential, branch-off, and de novo subtypes. Subtypes might be associated with clinical and pathologic features and be used to select surveillance programs for patients with IPMNs.

Original languageEnglish
Pages (from-to)647-661.e2
JournalGastroenterology
Volume156
Issue number3
DOIs
Publication statusPublished - 2019 Feb 1

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Pancreatic Neoplasms
Adenocarcinoma
Neoplasms
Mutation
Papillary Adenocarcinoma
Exome
Neoplasm Genes
Methylation
Disease-Free Survival
Clone Cells

Keywords

  • Pancreas
  • Progression Model
  • Risk Prediction
  • Tumorigenesis

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features. / Omori, Yuko; Ono, Yusuke; Tanino, Mishie; Karasaki, Hidenori; Yamaguchi, Hiroshi; Furukawa, Toru; Enomoto, Katsuro; Ueda, Jun; Sumi, Atsuko; Katayama, Jin; Muraki, Miho; Taniue, Kenzui; Takahashi, Kuniyuki; Ambo, Yoshiyasu; Shinohara, Toshiya; Nishihara, Hiroshi; Sasajima, Junpei; Maguchi, Hiroyuki; Mizukami, Yusuke; Okumura, Toshikatsu; Tanaka, Shinya.

In: Gastroenterology, Vol. 156, No. 3, 01.02.2019, p. 647-661.e2.

Research output: Contribution to journalArticle

Omori, Y, Ono, Y, Tanino, M, Karasaki, H, Yamaguchi, H, Furukawa, T, Enomoto, K, Ueda, J, Sumi, A, Katayama, J, Muraki, M, Taniue, K, Takahashi, K, Ambo, Y, Shinohara, T, Nishihara, H, Sasajima, J, Maguchi, H, Mizukami, Y, Okumura, T & Tanaka, S 2019, 'Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features', Gastroenterology, vol. 156, no. 3, pp. 647-661.e2. https://doi.org/10.1053/j.gastro.2018.10.029
Omori, Yuko ; Ono, Yusuke ; Tanino, Mishie ; Karasaki, Hidenori ; Yamaguchi, Hiroshi ; Furukawa, Toru ; Enomoto, Katsuro ; Ueda, Jun ; Sumi, Atsuko ; Katayama, Jin ; Muraki, Miho ; Taniue, Kenzui ; Takahashi, Kuniyuki ; Ambo, Yoshiyasu ; Shinohara, Toshiya ; Nishihara, Hiroshi ; Sasajima, Junpei ; Maguchi, Hiroyuki ; Mizukami, Yusuke ; Okumura, Toshikatsu ; Tanaka, Shinya. / Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features. In: Gastroenterology. 2019 ; Vol. 156, No. 3. pp. 647-661.e2.
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AU - Omori, Yuko

AU - Ono, Yusuke

AU - Tanino, Mishie

AU - Karasaki, Hidenori

AU - Yamaguchi, Hiroshi

AU - Furukawa, Toru

AU - Enomoto, Katsuro

AU - Ueda, Jun

AU - Sumi, Atsuko

AU - Katayama, Jin

AU - Muraki, Miho

AU - Taniue, Kenzui

AU - Takahashi, Kuniyuki

AU - Ambo, Yoshiyasu

AU - Shinohara, Toshiya

AU - Nishihara, Hiroshi

AU - Sasajima, Junpei

AU - Maguchi, Hiroyuki

AU - Mizukami, Yusuke

AU - Okumura, Toshikatsu

AU - Tanaka, Shinya

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N2 - Background & Aims: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about the mechanism of progression. This makes it challenging to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses. Methods: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs, and 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors. Results: We determined the clonal relatedness of lesions, based on driver mutations shared by PDAs and concurrent IPMNs, and classified the lesions into 3 subtypes. Twelve PDAs contained driver mutations shared by all concurrent IPMNs, which we called the sequential subtype. This subset was characterized by less diversity in incipient foci with frequent GNAS mutations. Eleven PDAs contained some driver mutations that were shared with concurrent IPMNs, which we called the branch-off subtype. In this subtype, PDAs and IPMNs had identical KRAS mutations but different GNAS mutations, although the lesions were adjacent. Whole-exome sequencing and methylation analysis of these lesions indicated clonal origin with later divergence. Ten PDAs had driver mutations not found in concurrent IPMNs, called the de novo subtype. Expression profiles of TP53 and SMAD4 increased our ability to differentiate these subtypes compared with sequencing data alone. The branch-off and de novo subtypes had substantial heterogeneity among early clones, such as differences in KRAS mutations. Patients with PDAs of the branch-off subtype had a longer times of disease-free survival than patients with PDAs of the de novo or the sequential subtypes. Conclusions: Detailed histologic and genetic analysis of PDAs and concurrent IPMNs identified 3 different pathways by which IPMNs progress to PDAs—we call these the sequential, branch-off, and de novo subtypes. Subtypes might be associated with clinical and pathologic features and be used to select surveillance programs for patients with IPMNs.

AB - Background & Aims: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about the mechanism of progression. This makes it challenging to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses. Methods: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs, and 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors. Results: We determined the clonal relatedness of lesions, based on driver mutations shared by PDAs and concurrent IPMNs, and classified the lesions into 3 subtypes. Twelve PDAs contained driver mutations shared by all concurrent IPMNs, which we called the sequential subtype. This subset was characterized by less diversity in incipient foci with frequent GNAS mutations. Eleven PDAs contained some driver mutations that were shared with concurrent IPMNs, which we called the branch-off subtype. In this subtype, PDAs and IPMNs had identical KRAS mutations but different GNAS mutations, although the lesions were adjacent. Whole-exome sequencing and methylation analysis of these lesions indicated clonal origin with later divergence. Ten PDAs had driver mutations not found in concurrent IPMNs, called the de novo subtype. Expression profiles of TP53 and SMAD4 increased our ability to differentiate these subtypes compared with sequencing data alone. The branch-off and de novo subtypes had substantial heterogeneity among early clones, such as differences in KRAS mutations. Patients with PDAs of the branch-off subtype had a longer times of disease-free survival than patients with PDAs of the de novo or the sequential subtypes. Conclusions: Detailed histologic and genetic analysis of PDAs and concurrent IPMNs identified 3 different pathways by which IPMNs progress to PDAs—we call these the sequential, branch-off, and de novo subtypes. Subtypes might be associated with clinical and pathologic features and be used to select surveillance programs for patients with IPMNs.

KW - Pancreas

KW - Progression Model

KW - Risk Prediction

KW - Tumorigenesis

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