Genomic characterization of malignant progression in neoplastic pancreatic cysts

Michaël Noë(Johns Hopkins University), Noushin Niknafs(Johns Hopkins University), Catherine G. Fischer(Johns Hopkins University), Wenzel M. Hackeng(Johns Hopkins University), Violeta Beleva Guthrie(Johns Hopkins University), Waki Hosoda(Johns Hopkins University), Marija Debeljak(Johns Hopkins University), Eniko Papp(Johns Hopkins University), Vilmos Adleff(Johns Hopkins University), James R. White(Johns Hopkins University), Claudio Luchini(University of Verona), Antonio Pea(University of Verona), Aldo Scarpa(University of Verona), Giovanni Butturini(Casa di Cura Villa Garda), Giuseppe Zamboni(University of Verona), M. Paola Castelli(Ospedale Sacro Cuore Don Calabria), Seung‐Mo Hong(Ulsan College), Shinichi Yachida(The University of Osaka), Nobuyoshi Hiraoka(Tokyo National Hospital), Anthony J. Gill(The University of Sydney), Jaswinder S. Samra(The University of Sydney), G. Johan A. Offerhaus(University Medical Center Utrecht), Anne Hoorens(Ghent University Hospital), Joanne Verheij(Amsterdam UMC Location University of Amsterdam), Casper Jansen(Thales (Netherlands)), Volkan Adsay(Koç University), Wei Jiang(Thomas Jefferson University), Jordan M. Winter(University Hospitals Seidman Cancer Center), Jorge Albores‐Saavedra(Hospital Médica Sur), Benoît Terris(Université Paris Cité), Elizabeth D. Thompson(Johns Hopkins University), Nicholas J. Roberts(Johns Hopkins University), Ralph H. Hruban(Johns Hopkins University), Rachel Karchin(Johns Hopkins University), Robert B. Scharpf(Johns Hopkins University), Lodewijk A.A. Brosens(Radboud University Nijmegen), Victor E. Velculescu(Johns Hopkins University), Laura D. Wood(Johns Hopkins University)
Nature Communications
August 14, 2020
10.1038/s41467-020-17917-8
Cited by 134Open Access
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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.

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