Tumor-Infiltrating Clonal Hematopoiesis

Oriol Pich; Elsa Bernard; Maria Zagorulya; Andrew Rowan; Constandina Pospori; Ramy Slama; Hector Huerga Encabo; Jennifer O'Sullivan; Despoina Papazoglou; Panayiotis Anastasiou; Chrysante S Iliakis; Sally-Ann Clark; Krijn K Dijkstra; Vittorio Barbè; Chris Bailey; Aaron J Stonestrom; Katey S S Enfield; Mary Green; Charlotte K Brierley; Alastair Magness; David R Pearce; Robert E Hynds; Rija Zaidi; Jayant K Rane; Ángel F Álvarez-Prado; Kerstin Thol; Rachel Scott; Supreet Kaur Bola; Elena Hoxha; Steve K Harris; Karl S Peggs; Sergio A Quezada; Allan Hackshaw; Simone Zaccaria; Johanna A Joyce; Ilaria Malanchi; Michael F Berger; Mariam Jamal-Hanjani; Andreas Wack; Julian Downward; William Grey; Cristina Lo Celso; Eva Grönroos; Charles M Rudin; Adam J Mead; Dominique Bonnet; Elli Papaemmanuil; Charles Swanton

doi:10.1056/NEJMoa2413361

Tumor-Infiltrating Clonal Hematopoiesis

Oriol Pich, Elsa Bernard, Maria Zagorulya, Andrew Rowan, Constandina Pospori, Ramy Slama, Hector Huerga Encabo, Jennifer O'Sullivan, Despoina Papazoglou, Panayiotis Anastasiou, Chrysante S Iliakis, Sally-Ann Clark, Krijn K Dijkstra, Vittorio Barbè, Chris Bailey, Aaron J Stonestrom, Katey S S Enfield, Mary Green, Charlotte K Brierley, Alastair MagnessDavid R Pearce, Robert E Hynds, Rija Zaidi, Jayant K Rane, Ángel F Álvarez-Prado, Kerstin Thol, Rachel Scott, Supreet Kaur Bola, Elena Hoxha, Steve K Harris, Karl S Peggs, Sergio A Quezada, Allan Hackshaw, Simone Zaccaria, Johanna A Joyce, Ilaria Malanchi, Michael F Berger, Mariam Jamal-Hanjani, Andreas Wack, Julian Downward, William Grey, Cristina Lo Celso, Eva Grönroos, Charles M Rudin, Adam J Mead, Dominique Bonnet, Elli Papaemmanuil, Charles Swanton

Department of Cancer Research

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

1 Citation (Scopus)

Abstract

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear.

METHODS: We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors.

RESULTS: Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth.

CONCLUSIONS: TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).

Original language	English
Pages (from-to)	1594-1608
Number of pages	15
Journal	New England Journal of Medicine
Volume	392
Issue number	16
DOIs	https://doi.org/10.1056/NEJMoa2413361 https://doi.org/10.1056/NEJMoa2413361
Publication status	Published - 23 Apr 2025

Keywords

Aged
Animals
Female
Humans
Male
Mice
Middle Aged
Carcinoma, Non-Small-Cell Lung/genetics
Clonal Hematopoiesis/genetics
Dioxygenases/genetics
DNA-Binding Proteins/genetics
Lung Neoplasms/genetics
Mutation
Neoplasm Recurrence, Local/epidemiology
Tumor Microenvironment/immunology
Monocytes/immunology
Cell Movement/genetics
Prospective Studies
Observational Studies as Topic
Cell Line, Tumor
Neoplasm Transplantation

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10.1056/NEJMoa2413361Licence: CC BY
10.1056/NEJMoa2413361

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Pich, O., Bernard, E., Zagorulya, M., Rowan, A., Pospori, C., Slama, R., Huerga Encabo, H., O'Sullivan, J., Papazoglou, D., Anastasiou, P., Iliakis, C. S., Clark, S.-A., Dijkstra, K. K., Barbè, V., Bailey, C., Stonestrom, A. J., Enfield, K. S. S., Green, M., Brierley, C. K., ... Swanton, C. (2025). Tumor-Infiltrating Clonal Hematopoiesis. New England Journal of Medicine, 392(16), 1594-1608. https://doi.org/10.1056/NEJMoa2413361, https://doi.org/10.1056/NEJMoa2413361

@article{6d6d4e1859cb4d528c5c9dead28ef716,

title = "Tumor-Infiltrating Clonal Hematopoiesis",

abstract = "BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear.METHODS: We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors.RESULTS: Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth.CONCLUSIONS: TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).",

keywords = "Aged, Animals, Female, Humans, Male, Mice, Middle Aged, Carcinoma, Non-Small-Cell Lung/genetics, Clonal Hematopoiesis/genetics, Dioxygenases/genetics, DNA-Binding Proteins/genetics, Lung Neoplasms/genetics, Mutation, Neoplasm Recurrence, Local/epidemiology, Tumor Microenvironment/immunology, Monocytes/immunology, Cell Movement/genetics, Prospective Studies, Observational Studies as Topic, Cell Line, Tumor, Neoplasm Transplantation",

author = "Oriol Pich and Elsa Bernard and Maria Zagorulya and Andrew Rowan and Constandina Pospori and Ramy Slama and {Huerga Encabo}, Hector and Jennifer O'Sullivan and Despoina Papazoglou and Panayiotis Anastasiou and Iliakis, {Chrysante S} and Sally-Ann Clark and Dijkstra, {Krijn K} and Vittorio Barb{\`e} and Chris Bailey and Stonestrom, {Aaron J} and Enfield, {Katey S S} and Mary Green and Brierley, {Charlotte K} and Alastair Magness and Pearce, {David R} and Hynds, {Robert E} and Rija Zaidi and Rane, {Jayant K} and {\'A}lvarez-Prado, {{\'A}ngel F} and Kerstin Thol and Rachel Scott and Bola, {Supreet Kaur} and Elena Hoxha and Harris, {Steve K} and Peggs, {Karl S} and Quezada, {Sergio A} and Allan Hackshaw and Simone Zaccaria and Joyce, {Johanna A} and Ilaria Malanchi and Berger, {Michael F} and Mariam Jamal-Hanjani and Andreas Wack and Julian Downward and William Grey and {Lo Celso}, Cristina and Eva Gr{\"o}nroos and Rudin, {Charles M} and Mead, {Adam J} and Dominique Bonnet and Elli Papaemmanuil and Charles Swanton",

note = "Copyright {\textcopyright} 2025 Massachusetts Medical Society.",

year = "2025",

month = apr,

day = "23",

doi = "10.1056/NEJMoa2413361",

language = "English",

volume = "392",

pages = "1594--1608",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "16",

}

Pich, O, Bernard, E, Zagorulya, M, Rowan, A, Pospori, C, Slama, R, Huerga Encabo, H, O'Sullivan, J, Papazoglou, D, Anastasiou, P, Iliakis, CS, Clark, S-A, Dijkstra, KK, Barbè, V, Bailey, C, Stonestrom, AJ, Enfield, KSS, Green, M, Brierley, CK, Magness, A, Pearce, DR, Hynds, RE, Zaidi, R, Rane, JK, Álvarez-Prado, ÁF, Thol, K, Scott, R, Bola, SK, Hoxha, E, Harris, SK, Peggs, KS, Quezada, SA, Hackshaw, A, Zaccaria, S, Joyce, JA, Malanchi, I, Berger, MF, Jamal-Hanjani, M, Wack, A, Downward, J, Grey, W, Lo Celso, C, Grönroos, E, Rudin, CM, Mead, AJ, Bonnet, D, Papaemmanuil, E & Swanton, C 2025, 'Tumor-Infiltrating Clonal Hematopoiesis', New England Journal of Medicine, vol. 392, no. 16, pp. 1594-1608. https://doi.org/10.1056/NEJMoa2413361, https://doi.org/10.1056/NEJMoa2413361

TY - JOUR

T1 - Tumor-Infiltrating Clonal Hematopoiesis

AU - Pich, Oriol

AU - Bernard, Elsa

AU - Zagorulya, Maria

AU - Rowan, Andrew

AU - Pospori, Constandina

AU - Slama, Ramy

AU - Huerga Encabo, Hector

AU - O'Sullivan, Jennifer

AU - Papazoglou, Despoina

AU - Anastasiou, Panayiotis

AU - Iliakis, Chrysante S

AU - Clark, Sally-Ann

AU - Dijkstra, Krijn K

AU - Barbè, Vittorio

AU - Bailey, Chris

AU - Stonestrom, Aaron J

AU - Enfield, Katey S S

AU - Green, Mary

AU - Brierley, Charlotte K

AU - Magness, Alastair

AU - Pearce, David R

AU - Hynds, Robert E

AU - Zaidi, Rija

AU - Rane, Jayant K

AU - Álvarez-Prado, Ángel F

AU - Thol, Kerstin

AU - Scott, Rachel

AU - Bola, Supreet Kaur

AU - Hoxha, Elena

AU - Harris, Steve K

AU - Peggs, Karl S

AU - Quezada, Sergio A

AU - Hackshaw, Allan

AU - Zaccaria, Simone

AU - Joyce, Johanna A

AU - Malanchi, Ilaria

AU - Berger, Michael F

AU - Jamal-Hanjani, Mariam

AU - Wack, Andreas

AU - Downward, Julian

AU - Grey, William

AU - Lo Celso, Cristina

AU - Grönroos, Eva

AU - Rudin, Charles M

AU - Mead, Adam J

AU - Bonnet, Dominique

AU - Papaemmanuil, Elli

AU - Swanton, Charles

PY - 2025/4/23

Y1 - 2025/4/23

N2 - BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear.METHODS: We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors.RESULTS: Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth.CONCLUSIONS: TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).

AB - BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear.METHODS: We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors.RESULTS: Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth.CONCLUSIONS: TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).

KW - Aged

KW - Animals

KW - Female

KW - Humans

KW - Male

KW - Mice

KW - Middle Aged

KW - Carcinoma, Non-Small-Cell Lung/genetics

KW - Clonal Hematopoiesis/genetics

KW - Dioxygenases/genetics

KW - DNA-Binding Proteins/genetics

KW - Lung Neoplasms/genetics

KW - Mutation

KW - Neoplasm Recurrence, Local/epidemiology

KW - Tumor Microenvironment/immunology

KW - Monocytes/immunology

KW - Cell Movement/genetics

KW - Prospective Studies

KW - Observational Studies as Topic

KW - Cell Line, Tumor

KW - Neoplasm Transplantation

UR - https://pubmed.ncbi.nlm.nih.gov/40267425/

U2 - 10.1056/NEJMoa2413361

DO - 10.1056/NEJMoa2413361

M3 - Article

C2 - 40267425

SN - 0028-4793

VL - 392

SP - 1594

EP - 1608

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 16

ER -

Tumor-Infiltrating Clonal Hematopoiesis

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