Dataset Information

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-naïve disease.See related commentary by Bednar and Pasca di Magliano, p. 762.This article is highlighted in the In This Issue feature, p. 747.

SUBMITTER: Sakamoto H

PROVIDER: S-EPMC7323937 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The Evolutionary Origins of Recurrent Pancreatic Cancer.

Sakamoto Hitomi H Attiyeh Marc A MA Gerold Jeffrey M JM Makohon-Moore Alvin P AP Hayashi Akimasa A Hong Jungeui J Kappagantula Rajya R Zhang Lance L Melchor Jerry P JP Reiter Johannes G JG Heyde Alexander A Bielski Craig M CM Penson Alexander V AV Gönen Mithat M Chakravarty Debyani D O'Reilly Eileen M EM Wood Laura D LD Hruban Ralph H RH Nowak Martin A MA Socci Nicholas D ND Taylor Barry S BS Iacobuzio-Donahue Christine A CA

Cancer discovery 20200319 6

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 mu ...[more]

PMID: 32193223

Similar Datasets

Project description:Background and aimsDespite the recent wealth of studies targeted at contact zones of cytotypes in various species, some aspects of polyploid evolution are still poorly understood. This is especially the case for the frequency and success rate of spontaneous neopolyploidization or the temporal dynamics of ploidy coexistence, requiring massive ploidy screening and repeated observations, respectively. To fill this gap, an extensive study of spatio-temporal patterns of ploidy coexistence was initiated in the widespread annual weed Tripleurospermum inodorum (Asteraceae).MethodsDNA flow cytometry along with confirmatory chromosome counts was employed to assess ploidy levels of 11?018 adult individuals and 1263 ex situ germinated seedlings from 1209 Central European populations. The ploidy screening was conducted across three spatial scales and supplemented with observations of temporal development of 37 mixed-ploidy populations.Key resultsThe contact zone between the diploid and tetraploid cytotypes has a diffuse, mosaic-like structure enabling common cytotype coexistence from the within-population to the landscape level. A marked difference in monoploid genome size between the two cytotypes enabled the easy distinction of neotetraploid mutants from long-established tetraploids. Neotetraploids were extremely rare (0·03?%) and occurred solitarily. Altogether five ploidy levels (2 x -6 x ) and several aneuploids were discovered; the diversity in nuclear DNA content was highest in early ontogenetic stages (seedlings) and among individuals from mixed-ploidy populations. In spite of profound temporal oscillations in cytotype frequencies in mixed-ploidy populations, both diploids and tetraploids usually persisted up to the last census.ConclusionsDiploids and tetraploids commonly coexist at all spatial scales and exhibit considerable temporal stability in local ploidy mixtures. Mixed-ploidy populations containing fertile triploid hybrids probaby act as effective generators of cytogenetic novelty and may facilitate inter-ploidy gene flow. Neopolyploid mutants were incapable of local establishment.

Dataset Information

The Evolutionary Origins of Recurrent Pancreatic Cancer.

Publications

The Evolutionary Origins of Recurrent Pancreatic Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets