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.
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.
Publisher Copyright:
© 2020, The Author(s).
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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U2 - 10.1038/s41467-020-17917-8
DO - 10.1038/s41467-020-17917-8
M3 - Article
C2 - 32796935
AN - SCOPUS:85089437148
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4085
ER -