The Evolutionary Origins of Recurrent Pancreatic Cancer
Open Access
- 18 March 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (6), 792-805
- https://doi.org/10.1158/2159-8290.CD-19-1508
Abstract
Surgery is the only curative option for stage I/II pancreatic cancer; nonetheless, most patients will experience a recurrence after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer, we performed whole-exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that recurrent disease after adjuvant or first-line platinum therapy corresponds to an increased mutational burden. Recurrent disease is enriched for genetic alterations predicted to activate MAPK/ERK and PI3K-AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment-induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In 1 patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings suggest routine post-treatment sampling may have value in the management of recurrent pancreatic cancer. SIGNIFICANCE: The biological features or clinical vulnerabilities of recurrent pancreatic cancer after pancreaticoduodenectomy are unknown. Using whole-exome sequencing we find that recurrent disease has a distinct genomic landscape, intermetastatic genetic heterogeneity, diverse clonal origins, and higher mutational burden than found for treatment-naive disease.Keywords
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Funding Information
- NIH NCI (R01 CA179991, R35 CA220508)
- NIH NCI (2T32 CA160001-06)
- Daiichi-Sankyo Foundation of Life Science
- Mochida Memorial Foundation for Medical and Pharmaceutical Research (R00 CA22999102)
- NIH NCI (P50 CA62924)
- National Cancer Institute (P30-CA008748)
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