Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer

Caitlin A. McIntyre; Adrien Grimont; Jiwoon Park; Yinuo Meng; Whitney J. Sisso; Kenneth Seier; Gun Ho Jang; Henry Walch; Victoria G. Aveson; David J. Falvo; William B. Fall; Christopher W. Chan; Andrew Wenger; Brett L. Ecker; Alessandra Pulvirenti; Rebecca Gelfer; Maria Paz Zafra; Nikolaus Schultz; Wungki Park; Eileen M. O'Reilly; Shauna L. Houlihan; Alicia Alonso; Erika Hissong; George M. Church; Christopher E. Mason; Despina Siolas; Faiyaz Notta; Mithat Gonen; Lukas E. Dow; William R. Jarnagin; Rohit Chandwani

doi:10.1016/j.ccell.2024.08.002

Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer

Caitlin A. McIntyre
, Adrien Grimont
, Jiwoon Park
, Yinuo Meng
, Whitney J. Sisso
, Kenneth Seier
, Gun Ho Jang
, Henry Walch
, Victoria G. Aveson
, David J. Falvo
, William B. Fall
, Christopher W. Chan
, Andrew Wenger
, Brett L. Ecker
, Alessandra Pulvirenti
, Rebecca Gelfer
, Maria Paz Zafra
, Nikolaus Schultz
, Wungki Park
, Eileen M. O'Reilly

Shauna L. Houlihan, Alicia Alonso, Erika Hissong, George M. Church, Christopher E. Mason, Despina Siolas, Faiyaz Notta, Mithat Gonen, Lukas E. Dow, William R. Jarnagin, Rohit Chandwani

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

34 Scopus citations

Abstract

KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRAS^G12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRAS^G12R tumors are associated with decreased distant recurrence and improved survival as compared to KRAS^G12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRAS^G12D and increased nuclear factor κB (NF-κB) signaling in KRAS^G12R tumors. Orthogonal studies of mouse Kras^G12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.

Original language	English (US)
Pages (from-to)	1614-1629.e5
Journal	Cancer Cell
Volume	42
Issue number	9
DOIs	https://doi.org/10.1016/j.ccell.2024.08.002
State	Published - Sep 9 2024
Externally published	Yes

Keywords

KRAS
clinical outcomes
genomics
organoids
pancreatic cancer
spatial transcriptomics

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2024.08.002

Cite this

McIntyre, C. A., Grimont, A., Park, J., Meng, Y., Sisso, W. J., Seier, K., Jang, G. H., Walch, H., Aveson, V. G., Falvo, D. J., Fall, W. B., Chan, C. W., Wenger, A., Ecker, B. L., Pulvirenti, A., Gelfer, R., Zafra, M. P., Schultz, N., Park, W., ... Chandwani, R. (2024). Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer. Cancer Cell, 42(9), 1614-1629.e5. https://doi.org/10.1016/j.ccell.2024.08.002

McIntyre, CA, Grimont, A, Park, J, Meng, Y, Sisso, WJ, Seier, K, Jang, GH, Walch, H, Aveson, VG, Falvo, DJ, Fall, WB, Chan, CW, Wenger, A, Ecker, BL, Pulvirenti, A, Gelfer, R, Zafra, MP, Schultz, N, Park, W, O'Reilly, EM, Houlihan, SL, Alonso, A, Hissong, E, Church, GM, Mason, CE, Siolas, D, Notta, F, Gonen, M, Dow, LE, Jarnagin, WR & Chandwani, R 2024, 'Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer', Cancer Cell, vol. 42, no. 9, pp. 1614-1629.e5. https://doi.org/10.1016/j.ccell.2024.08.002

@article{6c110ca7c80e4c739f0e38b28c28d802,

title = "Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer",

abstract = "KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRASG12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRASG12D and increased nuclear factor κB (NF-κB) signaling in KRASG12R tumors. Orthogonal studies of mouse KrasG12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.",

keywords = "KRAS, clinical outcomes, genomics, organoids, pancreatic cancer, spatial transcriptomics",

author = "McIntyre, \{Caitlin A.\} and Adrien Grimont and Jiwoon Park and Yinuo Meng and Sisso, \{Whitney J.\} and Kenneth Seier and Jang, \{Gun Ho\} and Henry Walch and Aveson, \{Victoria G.\} and Falvo, \{David J.\} and Fall, \{William B.\} and Chan, \{Christopher W.\} and Andrew Wenger and Ecker, \{Brett L.\} and Alessandra Pulvirenti and Rebecca Gelfer and Zafra, \{Maria Paz\} and Nikolaus Schultz and Wungki Park and O'Reilly, \{Eileen M.\} and Houlihan, \{Shauna L.\} and Alicia Alonso and Erika Hissong and Church, \{George M.\} and Mason, \{Christopher E.\} and Despina Siolas and Faiyaz Notta and Mithat Gonen and Dow, \{Lukas E.\} and Jarnagin, \{William R.\} and Rohit Chandwani",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2024",

month = sep,

day = "9",

doi = "10.1016/j.ccell.2024.08.002",

language = "English (US)",

volume = "42",

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T1 - Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer

AU - McIntyre, Caitlin A.

AU - Grimont, Adrien

AU - Park, Jiwoon

AU - Meng, Yinuo

AU - Sisso, Whitney J.

AU - Seier, Kenneth

AU - Jang, Gun Ho

AU - Walch, Henry

AU - Aveson, Victoria G.

AU - Falvo, David J.

AU - Fall, William B.

AU - Chan, Christopher W.

AU - Wenger, Andrew

AU - Ecker, Brett L.

AU - Pulvirenti, Alessandra

AU - Gelfer, Rebecca

AU - Zafra, Maria Paz

AU - Schultz, Nikolaus

AU - Park, Wungki

AU - O'Reilly, Eileen M.

AU - Houlihan, Shauna L.

AU - Alonso, Alicia

AU - Hissong, Erika

AU - Church, George M.

AU - Mason, Christopher E.

AU - Siolas, Despina

AU - Notta, Faiyaz

AU - Gonen, Mithat

AU - Dow, Lukas E.

AU - Jarnagin, William R.

AU - Chandwani, Rohit

PY - 2024/9/9

Y1 - 2024/9/9

N2 - KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRASG12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRASG12D and increased nuclear factor κB (NF-κB) signaling in KRASG12R tumors. Orthogonal studies of mouse KrasG12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.

AB - KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRASG12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRASG12D and increased nuclear factor κB (NF-κB) signaling in KRASG12R tumors. Orthogonal studies of mouse KrasG12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.

KW - KRAS

KW - clinical outcomes

KW - genomics

KW - organoids

KW - pancreatic cancer

KW - spatial transcriptomics

UR - https://www.scopus.com/pages/publications/85203874260

UR - https://www.scopus.com/pages/publications/85203874260#tab=citedBy

U2 - 10.1016/j.ccell.2024.08.002

DO - 10.1016/j.ccell.2024.08.002

M3 - Article

C2 - 39214094

AN - SCOPUS:85203874260

SN - 1535-6108

VL - 42

SP - 1614-1629.e5

JO - Cancer Cell

JF - Cancer Cell

IS - 9

ER -

Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer

Abstract

Keywords

ASJC Scopus subject areas

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