期刊
GASTROENTEROLOGY
卷 157, 期 4, 页码 1123-+出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2019.06.001
关键词
PDAC; carcinogenesis; driver gene; oncogene
资金
- National Institutes of Health/National Cancer Institute [P50 CA62924]
- National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [K08 DK107781]
- Sol Goldman Pancreatic Cancer Research Center
- Buffone Family Gastrointestinal Cancer Research Fund
- Kaya Tuncer Career Development Award in Gastrointestinal Cancer Prevention
- American Gastroenterological Association-Bernard Lee Schwartz Foundation Research Scholar Award in Pancreatic Cancer
- Sidney Kimmel Foundation for Cancer Research Kimmel Scholar Award
- American Association for Cancer Research-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
- Gerald O. Mann Charitable Foundation
- Lustgarten Foundation for Pancreatic Cancer Research
- Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences [2016-I2M-1-001]
BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS: We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.
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