Genomic characterization of malignant progression in neoplastic pancreatic cysts

Michaël Noë; Noushin Niknafs; Catherine G. Fischer; Wenzel M. Hackeng; Violeta Beleva Guthrie; Waki Hosoda; Marija Debeljak; Eniko Papp; Vilmos Adleff; James R. White; Claudio Luchini; Antonio Pea; Aldo Scarpa; Giovanni Butturini; Giuseppe Zamboni; Paola Castelli; Seung Mo Hong; Shinichi Yachida; Nobuyoshi Hiraoka; Anthony J. Gill; Jaswinder S. Samra; G. Johan A. Offerhaus; Anne Hoorens; Joanne Verheij; Casper Jansen; N. Volkan Adsay; Wei Jiang; Jordan Winter; Jorge Albores-Saavedra; Benoit Terris; Elizabeth D. Thompson; Nicholas J. Roberts; Ralph H. Hruban; Rachel Karchin; Robert B. Scharpf; Lodewijk A.A. Brosens; Victor E. Velculescu; Laura D. Wood

doi:10.1038/s41467-020-17917-8

Genomic characterization of malignant progression in neoplastic pancreatic cysts

Michaël Noë, Noushin Niknafs, Catherine G. Fischer, Wenzel M. Hackeng, Violeta Beleva Guthrie, Waki Hosoda, Marija Debeljak, Eniko Papp, Vilmos Adleff, James R. White, Claudio Luchini, Antonio Pea, Aldo Scarpa, Giovanni Butturini, Giuseppe Zamboni, Paola Castelli, Seung Mo Hong, Shinichi Yachida, Nobuyoshi Hiraoka, Anthony J. GillJaswinder S. Samra, G. Johan A. Offerhaus, Anne Hoorens, Joanne Verheij, Casper Jansen, N. Volkan Adsay, Wei Jiang, Jordan Winter, Jorge Albores-Saavedra, Benoit Terris, Elizabeth D. Thompson, Nicholas J. Roberts, Ralph H. Hruban, Rachel Karchin, Robert B. Scharpf, Lodewijk A.A. Brosens, Victor E. Velculescu, Laura D. Wood

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.

Original language	English (US)
Article number	4085
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17917-8
State	Published - Dec 1 2020

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Noë, M., Niknafs, N., Fischer, C. G., Hackeng, W. M., Beleva Guthrie, V., Hosoda, W., Debeljak, M., Papp, E., Adleff, V., White, J. R., Luchini, C., Pea, A., Scarpa, A., Butturini, G., Zamboni, G., Castelli, P., Hong, S. M., Yachida, S., Hiraoka, N., ... Wood, L. D. (2020). Genomic characterization of malignant progression in neoplastic pancreatic cysts. Nature communications, 11(1), [4085]. https://doi.org/10.1038/s41467-020-17917-8

Genomic characterization of malignant progression in neoplastic pancreatic cysts. / Noë, Michaël; Niknafs, Noushin; Fischer, Catherine G.; Hackeng, Wenzel M.; Beleva Guthrie, Violeta; Hosoda, Waki; Debeljak, Marija; Papp, Eniko; Adleff, Vilmos; White, James R.; Luchini, Claudio; Pea, Antonio; Scarpa, Aldo; Butturini, Giovanni; Zamboni, Giuseppe; Castelli, Paola; Hong, Seung Mo; Yachida, Shinichi; Hiraoka, Nobuyoshi; Gill, Anthony J.; Samra, Jaswinder S.; Offerhaus, G. Johan A.; Hoorens, Anne; Verheij, Joanne; Jansen, Casper; Adsay, N. Volkan; Jiang, Wei; Winter, Jordan; Albores-Saavedra, Jorge; Terris, Benoit; Thompson, Elizabeth D.; Roberts, Nicholas J.; Hruban, Ralph H.; Karchin, Rachel; Scharpf, Robert B.; Brosens, Lodewijk A.A.; Velculescu, Victor E.; Wood, Laura D.

In: Nature communications, Vol. 11, No. 1, 4085, 01.12.2020.

Research output: Contribution to journal › Article › peer-review

Noë, M, Niknafs, N, Fischer, CG, Hackeng, WM, Beleva Guthrie, V, Hosoda, W, Debeljak, M, Papp, E, Adleff, V, White, JR, Luchini, C, Pea, A, Scarpa, A, Butturini, G, Zamboni, G, Castelli, P, Hong, SM, Yachida, S, Hiraoka, N, Gill, AJ, Samra, JS, Offerhaus, GJA, Hoorens, A, Verheij, J, Jansen, C, Adsay, NV, Jiang, W, Winter, J, Albores-Saavedra, J, Terris, B, Thompson, ED , Roberts, NJ , Hruban, RH, Karchin, R, Scharpf, RB, Brosens, LAA, Velculescu, VE & Wood, LD 2020, 'Genomic characterization of malignant progression in neoplastic pancreatic cysts', Nature communications, vol. 11, no. 1, 4085. https://doi.org/10.1038/s41467-020-17917-8

Noë, Michaël ; Niknafs, Noushin ; Fischer, Catherine G. ; Hackeng, Wenzel M. ; Beleva Guthrie, Violeta ; Hosoda, Waki ; Debeljak, Marija ; Papp, Eniko ; Adleff, Vilmos ; White, James R. ; Luchini, Claudio ; Pea, Antonio ; Scarpa, Aldo ; Butturini, Giovanni ; Zamboni, Giuseppe ; Castelli, Paola ; Hong, Seung Mo ; Yachida, Shinichi ; Hiraoka, Nobuyoshi ; Gill, Anthony J. ; Samra, Jaswinder S. ; Offerhaus, G. Johan A. ; Hoorens, Anne ; Verheij, Joanne ; Jansen, Casper ; Adsay, N. Volkan ; Jiang, Wei ; Winter, Jordan ; Albores-Saavedra, Jorge ; Terris, Benoit ; Thompson, Elizabeth D. ; Roberts, Nicholas J. ; Hruban, Ralph H. ; Karchin, Rachel ; Scharpf, Robert B. ; Brosens, Lodewijk A.A. ; Velculescu, Victor E. ; Wood, Laura D. / Genomic characterization of malignant progression in neoplastic pancreatic cysts. In: Nature communications. 2020 ; Vol. 11, No. 1.

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title = "Genomic characterization of malignant progression in neoplastic pancreatic cysts",

abstract = "Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.",

author = "Micha{\"e}l No{\"e} and Noushin Niknafs and Fischer, {Catherine G.} and Hackeng, {Wenzel M.} and {Beleva Guthrie}, Violeta and Waki Hosoda and Marija Debeljak and Eniko Papp and Vilmos Adleff and White, {James R.} and Claudio Luchini and Antonio Pea and Aldo Scarpa and Giovanni Butturini and Giuseppe Zamboni and Paola Castelli and Hong, {Seung Mo} and Shinichi Yachida and Nobuyoshi Hiraoka and Gill, {Anthony J.} and Samra, {Jaswinder S.} and Offerhaus, {G. Johan A.} and Anne Hoorens and Joanne Verheij and Casper Jansen and Adsay, {N. Volkan} and Wei Jiang and Jordan Winter and Jorge Albores-Saavedra and Benoit Terris and Thompson, {Elizabeth D.} and Roberts, {Nicholas J.} and Hruban, {Ralph H.} and Rachel Karchin and Scharpf, {Robert B.} and Brosens, {Lodewijk A.A.} and Velculescu, {Victor E.} and Wood, {Laura D.}",

note = "Funding Information: The authors acknowledge the following sources of support: NIH/NCI P50 CA62924; NIH/NIDDK K08 DK107781; NIH/NCI R01 CA121113; NIH/NCI R00 CA190889; NIH/ NCI P30 CA006973; Sol Goldman Pancreatic Cancer Research Center; Buffone Family Gastrointestinal Cancer Research Fund; Carol S. and Robert M. Long Pancreatic Cancer Research Fund; Kaya Tuncer Career Development Award in Gastrointestinal Cancer Prevention; AGA-Bernard Lee Schwartz Foundation Research Scholar Award in Pancreatic Cancer; Sidney Kimmel Foundation for Cancer Research Kimmel Scholar Award; AACR-Incyte Corporation Career Development Award for Pancreatic Cancer Research; American Cancer Society Research Scholar Grant; Emerson Collective Cancer Research Fund; Rolfe Pancreatic Cancer Foundation; Joseph C Monastra Foundation; The Gerald O Mann Charitable Foundation (Harriet and Allan Wulfstat, Trustees); Susan Wojcicki and Denis Troper; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Dutch Digestive Foundation (MLDS CDG 14-02); Nijbakker-Morra Foundation; Lisa Waller Hayes Foundation; Avner Pancreatic Cancer Foundation. Funding Information: L.D.W. receives research funding from Applied Materials. V.E.V. is a founder of Personal Genome Diagnostics, a member of its Scientific Advisory Board and Board of Directors, and owns Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. V.E.V. is an advisor to Takeda Pharmaceuticals. Within the last five years, V.E.V. has been an advisor to Daiichi Sankyo, Janssen Diagnostics, and Ignyta. J.R.W. is founder and owner of Resphera Biosciences LLC, and is a consultant to Personal Genome Diagnostics Inc. The terms of these arrangements are managed by Johns Hopkins University in accordance with its conflict of interest policies. The other authors declare no conflict of interest.",

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doi = "10.1038/s41467-020-17917-8",

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AU - Noë, Michaël

AU - Niknafs, Noushin

AU - Fischer, Catherine G.

AU - Hackeng, Wenzel M.

AU - Beleva Guthrie, Violeta

AU - Hosoda, Waki

AU - Debeljak, Marija

AU - Papp, Eniko

AU - Adleff, Vilmos

AU - White, James R.

AU - Luchini, Claudio

AU - Pea, Antonio

AU - Scarpa, Aldo

AU - Butturini, Giovanni

AU - Zamboni, Giuseppe

AU - Castelli, Paola

AU - Hong, Seung Mo

AU - Yachida, Shinichi

AU - Hiraoka, Nobuyoshi

AU - Gill, Anthony J.

AU - Samra, Jaswinder S.

AU - Offerhaus, G. Johan A.

AU - Hoorens, Anne

AU - Verheij, Joanne

AU - Jansen, Casper

AU - Adsay, N. Volkan

AU - Jiang, Wei

AU - Winter, Jordan

AU - Albores-Saavedra, Jorge

AU - Terris, Benoit

AU - Thompson, Elizabeth D.

AU - Roberts, Nicholas J.

AU - Hruban, Ralph H.

AU - Karchin, Rachel

AU - Scharpf, Robert B.

AU - Brosens, Lodewijk A.A.

AU - Velculescu, Victor E.

AU - Wood, Laura D.

N1 - Funding Information: The authors acknowledge the following sources of support: NIH/NCI P50 CA62924; NIH/NIDDK K08 DK107781; NIH/NCI R01 CA121113; NIH/NCI R00 CA190889; NIH/ NCI P30 CA006973; Sol Goldman Pancreatic Cancer Research Center; Buffone Family Gastrointestinal Cancer Research Fund; Carol S. and Robert M. Long Pancreatic Cancer Research Fund; Kaya Tuncer Career Development Award in Gastrointestinal Cancer Prevention; AGA-Bernard Lee Schwartz Foundation Research Scholar Award in Pancreatic Cancer; Sidney Kimmel Foundation for Cancer Research Kimmel Scholar Award; AACR-Incyte Corporation Career Development Award for Pancreatic Cancer Research; American Cancer Society Research Scholar Grant; Emerson Collective Cancer Research Fund; Rolfe Pancreatic Cancer Foundation; Joseph C Monastra Foundation; The Gerald O Mann Charitable Foundation (Harriet and Allan Wulfstat, Trustees); Susan Wojcicki and Denis Troper; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Dutch Digestive Foundation (MLDS CDG 14-02); Nijbakker-Morra Foundation; Lisa Waller Hayes Foundation; Avner Pancreatic Cancer Foundation. Funding Information: L.D.W. receives research funding from Applied Materials. V.E.V. is a founder of Personal Genome Diagnostics, a member of its Scientific Advisory Board and Board of Directors, and owns Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. V.E.V. is an advisor to Takeda Pharmaceuticals. Within the last five years, V.E.V. has been an advisor to Daiichi Sankyo, Janssen Diagnostics, and Ignyta. J.R.W. is founder and owner of Resphera Biosciences LLC, and is a consultant to Personal Genome Diagnostics Inc. The terms of these arrangements are managed by Johns Hopkins University in accordance with its conflict of interest policies. The other authors declare no conflict of interest.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.

AB - Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.

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