The Evolutionary Forest of Pancreatic Cancer

Katelyn M. Mullen; Jungeui Hong; Marc A. Attiyeh; Akimasa Hayashi; Hitomi Sakamoto; Zachary A. Kohutek; Caitlin A. McIntyre; Haochen Zhang; Alvin P. Makohon-Moore; Amanda Zucker; Laura D. Wood; Matthew A. Myers; Brian J. Arnold; Simone Zaccaria; Joanne F. Chou; Marinela Capanu; Nicholas D. Socci; Benjamin J. Raphael; Christine A. Iacobuzio-Donahue

doi:10.1158/2159-8290.CD-23-1541

The Evolutionary Forest of Pancreatic Cancer

Katelyn M. Mullen, Jungeui Hong, Marc A. Attiyeh, Akimasa Hayashi, Hitomi Sakamoto, Zachary A. Kohutek, Caitlin A. McIntyre, Haochen Zhang, Alvin P. Makohon-Moore, Amanda Zucker, Laura D. Wood, Matthew A. Myers, Brian J. Arnold, Simone Zaccaria, Joanne F. Chou, Marinela Capanu, Nicholas D. Socci, Benjamin J. Raphael, Christine A. Iacobuzio-Donahue

Center for Discovery and Innovation

Hackensack Meridian School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which these features occur remain unexplored. We studied genome landscapes, phylogenies, and clonal compositions of 91 PDACs in relation to clinicopathologic features. There was no difference in the number of driver mutations or evolutionary timing when each mutation occurred. High truncal density, a metric of the accumulation of somatic mutations in the lineage that gave rise to each PDAC, was significantly associated with worse overall survival. Polyclonal, monoclonal, or mixed polyclonal/monoclonal metastases were identified across the cohort, highlighting multiple forms of intertumoral heterogeneity. Advanced stage and treated PDACs had higher odds of being polyclonal, whereas oligometastatic PDACs had fewer driver alterations, a lower fractional allelic loss, and increased likelihood of being monoclonal. In sum, our findings reveal novel insights into the dynamic nature of the PDAC genome beyond established genetic paradigms. Significance: Although the pancreatic cancer genome has been described, it has not been explored with respect to stages of diagnosis or treatment bottlenecks. We now describe and quantify the genomic features of PDAC in the context of evolutionary metrics and in doing so have identified a novel prognostic biomarker.

Original language	American English
Pages (from-to)	329-345
Number of pages	17
Journal	Cancer Discovery
Volume	15
Issue number	2
DOIs	https://doi.org/10.1158/2159-8290.CD-23-1541
State	Published - Feb 1 2025

ASJC Scopus subject areas

Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/2159-8290.CD-23-1541

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Mullen, K. M., Hong, J., Attiyeh, M. A., Hayashi, A., Sakamoto, H., Kohutek, Z. A., McIntyre, C. A., Zhang, H., Makohon-Moore, A. P., Zucker, A., Wood, L. D., Myers, M. A., Arnold, B. J., Zaccaria, S., Chou, J. F., Capanu, M., Socci, N. D., Raphael, B. J., & Iacobuzio-Donahue, C. A. (2025). The Evolutionary Forest of Pancreatic Cancer. Cancer Discovery, 15(2), 329-345. https://doi.org/10.1158/2159-8290.CD-23-1541

@article{9b4ccfc4c38a4006a4ec9d341deea7a7,

title = "The Evolutionary Forest of Pancreatic Cancer",

abstract = "The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which these features occur remain unexplored. We studied genome landscapes, phylogenies, and clonal compositions of 91 PDACs in relation to clinicopathologic features. There was no difference in the number of driver mutations or evolutionary timing when each mutation occurred. High truncal density, a metric of the accumulation of somatic mutations in the lineage that gave rise to each PDAC, was significantly associated with worse overall survival. Polyclonal, monoclonal, or mixed polyclonal/monoclonal metastases were identified across the cohort, highlighting multiple forms of intertumoral heterogeneity. Advanced stage and treated PDACs had higher odds of being polyclonal, whereas oligometastatic PDACs had fewer driver alterations, a lower fractional allelic loss, and increased likelihood of being monoclonal. In sum, our findings reveal novel insights into the dynamic nature of the PDAC genome beyond established genetic paradigms. Significance: Although the pancreatic cancer genome has been described, it has not been explored with respect to stages of diagnosis or treatment bottlenecks. We now describe and quantify the genomic features of PDAC in the context of evolutionary metrics and in doing so have identified a novel prognostic biomarker.",

author = "Mullen, {Katelyn M.} and Jungeui Hong and Attiyeh, {Marc A.} and Akimasa Hayashi and Hitomi Sakamoto and Kohutek, {Zachary A.} and McIntyre, {Caitlin A.} and Haochen Zhang and Makohon-Moore, {Alvin P.} and Amanda Zucker and Wood, {Laura D.} and Myers, {Matthew A.} and Arnold, {Brian J.} and Simone Zaccaria and Chou, {Joanne F.} and Marinela Capanu and Socci, {Nicholas D.} and Raphael, {Benjamin J.} and Iacobuzio-Donahue, {Christine A.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors.",

year = "2025",

month = feb,

day = "1",

doi = "10.1158/2159-8290.CD-23-1541",

language = "American English",

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Mullen, KM, Hong, J, Attiyeh, MA, Hayashi, A, Sakamoto, H, Kohutek, ZA, McIntyre, CA, Zhang, H, Makohon-Moore, AP, Zucker, A, Wood, LD, Myers, MA, Arnold, BJ, Zaccaria, S, Chou, JF, Capanu, M, Socci, ND, Raphael, BJ & Iacobuzio-Donahue, CA 2025, 'The Evolutionary Forest of Pancreatic Cancer', Cancer Discovery, vol. 15, no. 2, pp. 329-345. https://doi.org/10.1158/2159-8290.CD-23-1541

TY - JOUR

T1 - The Evolutionary Forest of Pancreatic Cancer

AU - Mullen, Katelyn M.

AU - Hong, Jungeui

AU - Attiyeh, Marc A.

AU - Hayashi, Akimasa

AU - Sakamoto, Hitomi

AU - Kohutek, Zachary A.

AU - McIntyre, Caitlin A.

AU - Zhang, Haochen

AU - Makohon-Moore, Alvin P.

AU - Zucker, Amanda

AU - Wood, Laura D.

AU - Myers, Matthew A.

AU - Arnold, Brian J.

AU - Zaccaria, Simone

AU - Chou, Joanne F.

AU - Capanu, Marinela

AU - Socci, Nicholas D.

AU - Raphael, Benjamin J.

AU - Iacobuzio-Donahue, Christine A.

PY - 2025/2/1

Y1 - 2025/2/1

N2 - The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which these features occur remain unexplored. We studied genome landscapes, phylogenies, and clonal compositions of 91 PDACs in relation to clinicopathologic features. There was no difference in the number of driver mutations or evolutionary timing when each mutation occurred. High truncal density, a metric of the accumulation of somatic mutations in the lineage that gave rise to each PDAC, was significantly associated with worse overall survival. Polyclonal, monoclonal, or mixed polyclonal/monoclonal metastases were identified across the cohort, highlighting multiple forms of intertumoral heterogeneity. Advanced stage and treated PDACs had higher odds of being polyclonal, whereas oligometastatic PDACs had fewer driver alterations, a lower fractional allelic loss, and increased likelihood of being monoclonal. In sum, our findings reveal novel insights into the dynamic nature of the PDAC genome beyond established genetic paradigms. Significance: Although the pancreatic cancer genome has been described, it has not been explored with respect to stages of diagnosis or treatment bottlenecks. We now describe and quantify the genomic features of PDAC in the context of evolutionary metrics and in doing so have identified a novel prognostic biomarker.

AB - The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which these features occur remain unexplored. We studied genome landscapes, phylogenies, and clonal compositions of 91 PDACs in relation to clinicopathologic features. There was no difference in the number of driver mutations or evolutionary timing when each mutation occurred. High truncal density, a metric of the accumulation of somatic mutations in the lineage that gave rise to each PDAC, was significantly associated with worse overall survival. Polyclonal, monoclonal, or mixed polyclonal/monoclonal metastases were identified across the cohort, highlighting multiple forms of intertumoral heterogeneity. Advanced stage and treated PDACs had higher odds of being polyclonal, whereas oligometastatic PDACs had fewer driver alterations, a lower fractional allelic loss, and increased likelihood of being monoclonal. In sum, our findings reveal novel insights into the dynamic nature of the PDAC genome beyond established genetic paradigms. Significance: Although the pancreatic cancer genome has been described, it has not been explored with respect to stages of diagnosis or treatment bottlenecks. We now describe and quantify the genomic features of PDAC in the context of evolutionary metrics and in doing so have identified a novel prognostic biomarker.

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U2 - 10.1158/2159-8290.CD-23-1541

DO - 10.1158/2159-8290.CD-23-1541

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C2 - 39378050

SN - 2159-8274

VL - 15

SP - 329

EP - 345

JO - Cancer Discovery

JF - Cancer Discovery

IS - 2

ER -

The Evolutionary Forest of Pancreatic Cancer

Abstract

ASJC Scopus subject areas

UN SDGs

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