Clonal Hematopoiesis Before, During, and After Human Spaceflight

Nuria Mencia Trinchant; Matthew J. MacKay; Christopher Chin; Ebrahim Afshinnekoo; Jonathan Foox; Cem Meydan; Daniel Butler; Christopher Mozsary; Nicholas A. Vernice; Charlotte Darby; Michael C. Schatz; Susan M. Bailey; Ari M. Melnick; Monica Guzman; Kelly Bolton; Lior Z. Braunstein; Francine Garrett-Bakelman; Ross L. Levine; Duane Hassane; Christopher E. Mason

doi:10.1016/j.celrep.2020.108458

Clonal Hematopoiesis Before, During, and After Human Spaceflight

Nuria Mencia Trinchant, Matthew J. MacKay, Christopher Chin, Ebrahim Afshinnekoo, Jonathan Foox, Cem Meydan, Daniel Butler, Christopher Mozsary, Nicholas A. Vernice, Charlotte Darby, Michael C. Schatz, Susan M. Bailey, Ari M. Melnick, Monica Guzman, Kelly Bolton, Lior Z. Braunstein, Francine Garrett-Bakelman, Ross L. Levine, Duane Hassane, Christopher E. Mason

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11 Scopus citations

Abstract

Clonal hematopoiesis (CH) occurs when blood cells harboring an advantageous mutation propagate faster than others. These mutations confer a risk for hematological cancers and cardiovascular disease. Here, we analyze CH in blood samples from a pair of twin astronauts over 4 years in bulk and fractionated cell populations using a targeted CH panel, linked-read whole-genome sequencing, and deep RNA sequencing. We show CH with distinct mutational profiles and increasing allelic fraction that includes a high-risk, TET2 clone in one subject and two DNMT3A mutations on distinct alleles in the other twin. These astronauts exhibit CH almost two decades prior to the mean age at which it is typically detected and show larger shifts in clone size than age-matched controls or radiotherapy patients, based on a longitudinal cohort of 157 cancer patients. As such, longitudinal monitoring of CH may serve as an important metric for overall cancer and cardiovascular risk in astronauts.

Original language	English
Article number	108458
Journal	Cell Reports
Volume	33
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2020.108458
State	Published - Dec 8 2020

Keywords

CHIP
DNMT3A
NASA
TET2
astronaut
clonal hematopoiesis
radiation
variant allele frequency

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10.1016/j.celrep.2020.108458

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Trinchant, N. M., MacKay, M. J., Chin, C., Afshinnekoo, E., Foox, J., Meydan, C., Butler, D., Mozsary, C., Vernice, N. A., Darby, C., Schatz, M. C., Bailey, S. M., Melnick, A. M., Guzman, M., Bolton, K., Braunstein, L. Z., Garrett-Bakelman, F., Levine, R. L., Hassane, D., & Mason, C. E. (2020). Clonal Hematopoiesis Before, During, and After Human Spaceflight. Cell Reports, 33(10), [108458]. https://doi.org/10.1016/j.celrep.2020.108458

@article{219378ce3dd540278b07d5d97a07c4a0,

title = "Clonal Hematopoiesis Before, During, and After Human Spaceflight",

abstract = "Clonal hematopoiesis (CH) occurs when blood cells harboring an advantageous mutation propagate faster than others. These mutations confer a risk for hematological cancers and cardiovascular disease. Here, we analyze CH in blood samples from a pair of twin astronauts over 4 years in bulk and fractionated cell populations using a targeted CH panel, linked-read whole-genome sequencing, and deep RNA sequencing. We show CH with distinct mutational profiles and increasing allelic fraction that includes a high-risk, TET2 clone in one subject and two DNMT3A mutations on distinct alleles in the other twin. These astronauts exhibit CH almost two decades prior to the mean age at which it is typically detected and show larger shifts in clone size than age-matched controls or radiotherapy patients, based on a longitudinal cohort of 157 cancer patients. As such, longitudinal monitoring of CH may serve as an important metric for overall cancer and cardiovascular risk in astronauts.",

keywords = "CHIP, DNMT3A, NASA, TET2, astronaut, clonal hematopoiesis, radiation, variant allele frequency",

author = "Trinchant, {Nuria Mencia} and MacKay, {Matthew J.} and Christopher Chin and Ebrahim Afshinnekoo and Jonathan Foox and Cem Meydan and Daniel Butler and Christopher Mozsary and Vernice, {Nicholas A.} and Charlotte Darby and Schatz, {Michael C.} and Bailey, {Susan M.} and Melnick, {Ari M.} and Monica Guzman and Kelly Bolton and Braunstein, {Lior Z.} and Francine Garrett-Bakelman and Levine, {Ross L.} and Duane Hassane and Mason, {Christopher E.}",

note = "Funding Information: The study was supported by NASA /TRISH grants (NNX14AH51G, NNX17AB26G, NNX16AO69A:0107, NNX16AO69A:0061), as well as the Bert L and N Kuggie Vallee Foundation , Igor Tulchinsky and the WorldQuant Foundation , and The Pershing Square Sohn Cancer Research Alliance (Mason). We also want to thank Bill Ackman and Olivia Flatto for their support. We would also like to thank the Genomics, Epigenomics, and Applied Bioinformatics Core Facilities at Weill Cornell Medicine for sequencing and data services. We would like to thank Chaithanya Ponnaluri, Eileen Dimalanta, Brittany Sexton, and Bradley W. Langhorst from New England Biolabs for their awesome collaboration in conducting these experiments, sequencing, and analysis. Funding Information: The study was supported by NASA/TRISH grants (NNX14AH51G, NNX17AB26G, NNX16AO69A:0107, NNX16AO69A:0061), as well as the Bert L and N Kuggie Vallee Foundation, Igor Tulchinsky and the WorldQuant Foundation, and The Pershing Square Sohn Cancer Research Alliance (Mason). We also want to thank Bill Ackman and Olivia Flatto for their support. We would also like to thank the Genomics, Epigenomics, and Applied Bioinformatics Core Facilities at Weill Cornell Medicine for sequencing and data services. We would like to thank Chaithanya Ponnaluri, Eileen Dimalanta, Brittany Sexton, and Bradley W. Langhorst from New England Biolabs for their awesome collaboration in conducting these experiments, sequencing, and analysis. C.E.M. and D.H. conceived of the study and funded the work. N.M.T. performed the capture and helped with analysis, along with D.B. S.M.B. C.C. J.F, F.G.-B. E.A. M.J.M. M.G. and C. Meydan and C. Mozsary. M.C.S. J.F. and C.D. helped with variant analysis. All authors read and approved the manuscript. No relevant conflicts apply to this work, but C.E.M. is a cofounder of Onegevity and Biotia. D.H. and C.E.M. also have positions at Tempus Labs. Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

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doi = "10.1016/j.celrep.2020.108458",

language = "English",

volume = "33",

journal = "Cell Reports",

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Trinchant, NM, MacKay, MJ, Chin, C, Afshinnekoo, E, Foox, J, Meydan, C, Butler, D, Mozsary, C, Vernice, NA, Darby, C, Schatz, MC, Bailey, SM, Melnick, AM, Guzman, M, Bolton, K, Braunstein, LZ, Garrett-Bakelman, F, Levine, RL, Hassane, D & Mason, CE 2020, 'Clonal Hematopoiesis Before, During, and After Human Spaceflight', Cell Reports, vol. 33, no. 10, 108458. https://doi.org/10.1016/j.celrep.2020.108458

TY - JOUR

T1 - Clonal Hematopoiesis Before, During, and After Human Spaceflight

AU - Trinchant, Nuria Mencia

AU - MacKay, Matthew J.

AU - Chin, Christopher

AU - Afshinnekoo, Ebrahim

AU - Foox, Jonathan

AU - Meydan, Cem

AU - Butler, Daniel

AU - Mozsary, Christopher

AU - Vernice, Nicholas A.

AU - Darby, Charlotte

AU - Schatz, Michael C.

AU - Bailey, Susan M.

AU - Melnick, Ari M.

AU - Guzman, Monica

AU - Bolton, Kelly

AU - Braunstein, Lior Z.

AU - Garrett-Bakelman, Francine

AU - Levine, Ross L.

AU - Hassane, Duane

AU - Mason, Christopher E.

N1 - Funding Information: The study was supported by NASA /TRISH grants (NNX14AH51G, NNX17AB26G, NNX16AO69A:0107, NNX16AO69A:0061), as well as the Bert L and N Kuggie Vallee Foundation , Igor Tulchinsky and the WorldQuant Foundation , and The Pershing Square Sohn Cancer Research Alliance (Mason). We also want to thank Bill Ackman and Olivia Flatto for their support. We would also like to thank the Genomics, Epigenomics, and Applied Bioinformatics Core Facilities at Weill Cornell Medicine for sequencing and data services. We would like to thank Chaithanya Ponnaluri, Eileen Dimalanta, Brittany Sexton, and Bradley W. Langhorst from New England Biolabs for their awesome collaboration in conducting these experiments, sequencing, and analysis. Funding Information: The study was supported by NASA/TRISH grants (NNX14AH51G, NNX17AB26G, NNX16AO69A:0107, NNX16AO69A:0061), as well as the Bert L and N Kuggie Vallee Foundation, Igor Tulchinsky and the WorldQuant Foundation, and The Pershing Square Sohn Cancer Research Alliance (Mason). We also want to thank Bill Ackman and Olivia Flatto for their support. We would also like to thank the Genomics, Epigenomics, and Applied Bioinformatics Core Facilities at Weill Cornell Medicine for sequencing and data services. We would like to thank Chaithanya Ponnaluri, Eileen Dimalanta, Brittany Sexton, and Bradley W. Langhorst from New England Biolabs for their awesome collaboration in conducting these experiments, sequencing, and analysis. C.E.M. and D.H. conceived of the study and funded the work. N.M.T. performed the capture and helped with analysis, along with D.B. S.M.B. C.C. J.F, F.G.-B. E.A. M.J.M. M.G. and C. Meydan and C. Mozsary. M.C.S. J.F. and C.D. helped with variant analysis. All authors read and approved the manuscript. No relevant conflicts apply to this work, but C.E.M. is a cofounder of Onegevity and Biotia. D.H. and C.E.M. also have positions at Tempus Labs. Publisher Copyright: © 2020 The Author(s)

PY - 2020/12/8

Y1 - 2020/12/8

N2 - Clonal hematopoiesis (CH) occurs when blood cells harboring an advantageous mutation propagate faster than others. These mutations confer a risk for hematological cancers and cardiovascular disease. Here, we analyze CH in blood samples from a pair of twin astronauts over 4 years in bulk and fractionated cell populations using a targeted CH panel, linked-read whole-genome sequencing, and deep RNA sequencing. We show CH with distinct mutational profiles and increasing allelic fraction that includes a high-risk, TET2 clone in one subject and two DNMT3A mutations on distinct alleles in the other twin. These astronauts exhibit CH almost two decades prior to the mean age at which it is typically detected and show larger shifts in clone size than age-matched controls or radiotherapy patients, based on a longitudinal cohort of 157 cancer patients. As such, longitudinal monitoring of CH may serve as an important metric for overall cancer and cardiovascular risk in astronauts.

AB - Clonal hematopoiesis (CH) occurs when blood cells harboring an advantageous mutation propagate faster than others. These mutations confer a risk for hematological cancers and cardiovascular disease. Here, we analyze CH in blood samples from a pair of twin astronauts over 4 years in bulk and fractionated cell populations using a targeted CH panel, linked-read whole-genome sequencing, and deep RNA sequencing. We show CH with distinct mutational profiles and increasing allelic fraction that includes a high-risk, TET2 clone in one subject and two DNMT3A mutations on distinct alleles in the other twin. These astronauts exhibit CH almost two decades prior to the mean age at which it is typically detected and show larger shifts in clone size than age-matched controls or radiotherapy patients, based on a longitudinal cohort of 157 cancer patients. As such, longitudinal monitoring of CH may serve as an important metric for overall cancer and cardiovascular risk in astronauts.

KW - CHIP

KW - DNMT3A

KW - NASA

KW - TET2

KW - astronaut

KW - clonal hematopoiesis

KW - radiation

KW - variant allele frequency

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U2 - 10.1016/j.celrep.2020.108458

DO - 10.1016/j.celrep.2020.108458

M3 - Article

C2 - 33242405

AN - SCOPUS:85097456165

SN - 2211-1247

VL - 33

JO - Cell Reports

JF - Cell Reports

IS - 10

M1 - 108458

ER -

Clonal Hematopoiesis Before, During, and After Human Spaceflight

Abstract

Keywords

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