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:https://doi.org/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

Pathology (AMC)

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

69 Citations (Scopus)

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
Article number	4085
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17917-8
Publication status	Published - 1 Dec 2020

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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), Article 4085. https://doi.org/10.1038/s41467-020-17917-8

@article{551cd70aba4840edab979141f1d513ec,

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 Seung-Mo Hong 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.}",

year = "2020",

month = dec,

day = "1",

doi = "https://doi.org/10.1038/s41467-020-17917-8",

language = "English",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

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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, S-M, 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

TY - JOUR

T1 - Genomic characterization of malignant progression in neoplastic pancreatic cysts

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85089437148&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/s41467-020-17917-8

DO - https://doi.org/10.1038/s41467-020-17917-8

M3 - Article

C2 - 32796935

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4085

ER -

Genomic characterization of malignant progression in neoplastic pancreatic cysts

Abstract

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