The evolutionary origins of recurrent pancreatic cancer Journal Article
| Authors: | Sakamoto, H.; Attiyeh, M. A.; Gerold, J. M.; Makohon-Moore, A. P.; Hayashi, A.; Hong, J.; Kappagantula, R.; Zhang, L.; Melchor, J. P.; Reiter, J. G.; Heyde, A.; Bielski, C. M.; Penson, A. V.; Gönen, M.; Chakravarty, D.; O'Reilly, E. M.; Wood, L. D.; Hruban, R. H.; Nowak, M. A.; Socci, N. D.; Taylor, B. S.; Iacobuzio-Donahue, C. A. |
| Article Title: | The evolutionary origins of recurrent pancreatic cancer |
| 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: | metastasis; carcinoma; resection; long-term survivors; repair; mutations; heterogeneity; signatures; rates; driver |
| Journal Title: | Cancer Discovery |
| Volume: | 10 |
| Issue: | 6 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2020-06-01 |
| Start Page: | 792 |
| End Page: | 805 |
| Language: | English |
| ACCESSION: | WOS:000537841600023 |
| DOI: | 10.1158/2159-8290.Cd-19-1508 |
| PROVIDER: | wos |
| PMCID: | PMC7323937 |
| PUBMED: | 32193223 |
| Notes: | Article -- Source: Wos |
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