Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-17917-8
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Funding
- NIH/NCI [P50 CA62924, R00 CA190889, P30 CA006973, R01 CA121113]
- NIH/NIDDK [K08 DK107781]
- 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
- Gerald O Mann Charitable Foundation
- Dutch Digestive Foundation [MLDS CDG 14-02]
- Nijbakker-Morra Foundation
- Avner Pancreatic Cancer Foundation
- Lisa Waller Hayes Foundation
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
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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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