Concordance for clonal hematopoiesis is limited in elderly twins

Margarete Alice Fabre; Thomas McKerrell; Maximillian Zwiebel; M S Vijayabaskar; Naomi Rachel Park; Philippa M Wells; Roland Rad; Panagiotis Deloukas; Kerrin S Small; Claire J Steves; George S Vassiliou

doi:10.1182/blood.2019001807

Concordance for clonal hematopoiesis is limited in elderly twins

Margarete Alice Fabre, Thomas McKerrell, Maximillian Zwiebel, M S Vijayabaskar, Naomi Rachel Park, Philippa M Wells, Roland Rad, Panagiotis Deloukas, Kerrin S Small, Claire J Steves, George S Vassiliou

Twin Research & Genetic Epidemiology

Wellcome Trust Sanger Institute, Human Genetics, Hinxton, Cambridge, United Kingdom; NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, United Kingdom; University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, United Kingdom.
German Consortium for Translational Cancer Research, Munich, Germany.
Department of Ageing & Health, St Thomas' Hospital, London, United Kingdom; Department of Stroke Medicine, King's College Hospital, London, United Kingdom; Department of Health and Social Care Research, King's College London, London, United Kingdom.
Technical University of Munich
Centre for Cancer Prevention, Queen Mary University of London, London, United Kingdom [email protected] [email protected].

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

34 Citations (Scopus)

Abstract

Although acquisition of leukemia-associated somatic mutations by 1 or more hematopoietic stem cells is inevitable with advancing age, its consequences are highly variable, ranging from clinically silent clonal hematopoiesis (CH) to leukemic progression. To investigate the influence of heritable factors on CH, we performed deep targeted sequencing of blood DNA from 52 monozygotic (MZ) and 27 dizygotic (DZ) twin pairs (aged 70-99 years). Using this highly sensitive approach, we identified CH (variant allele frequency ≥0.5%) in 62% of individuals. We did not observe higher concordance for CH within MZ twin pairs as compared with that within DZ twin pairs, or to that expected by chance. However, we did identify 2 MZ pairs in which both twins harbored identical rare somatic mutations, suggesting a shared cell of origin. Finally, in 3 MZ twin pairs harboring mutations in the same driver genes, serial blood samples taken 4 to 5 years apart showed substantial twin-to-twin variability in clonal trajectories. Our findings propose that the inherited genome does not exert a dominant influence on the behavior of adult CH and provide evidence that CH mutations may be acquired in utero.

Original language	English
Pages (from-to)	269-273
Number of pages	5
Journal	Blood
Volume	135
Issue number	4
Early online date	25 Oct 2019
DOIs	https://doi.org/10.1182/blood.2019001807
Publication status	Published - 23 Jan 2020

UN SDGs

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

Access to Document

10.1182/blood.2019001807

Cite this

@article{bc8ff8e58dbb472f91d7e4b5cce750ac,

title = "Concordance for clonal hematopoiesis is limited in elderly twins",

abstract = "Although acquisition of leukemia-associated somatic mutations by 1 or more hematopoietic stem cells is inevitable with advancing age, its consequences are highly variable, ranging from clinically silent clonal hematopoiesis (CH) to leukemic progression. To investigate the influence of heritable factors on CH, we performed deep targeted sequencing of blood DNA from 52 monozygotic (MZ) and 27 dizygotic (DZ) twin pairs (aged 70-99 years). Using this highly sensitive approach, we identified CH (variant allele frequency ≥0.5%) in 62% of individuals. We did not observe higher concordance for CH within MZ twin pairs as compared with that within DZ twin pairs, or to that expected by chance. However, we did identify 2 MZ pairs in which both twins harbored identical rare somatic mutations, suggesting a shared cell of origin. Finally, in 3 MZ twin pairs harboring mutations in the same driver genes, serial blood samples taken 4 to 5 years apart showed substantial twin-to-twin variability in clonal trajectories. Our findings propose that the inherited genome does not exert a dominant influence on the behavior of adult CH and provide evidence that CH mutations may be acquired in utero.",

author = "Fabre, {Margarete Alice} and Thomas McKerrell and Maximillian Zwiebel and Vijayabaskar, {M S} and Park, {Naomi Rachel} and Wells, {Philippa M} and Roland Rad and Panagiotis Deloukas and Small, {Kerrin S} and Steves, {Claire J} and Vassiliou, {George S}",

note = "Copyright {\textcopyright} 2019 American Society of Hematology.",

year = "2020",

month = jan,

day = "23",

doi = "10.1182/blood.2019001807",

language = "English",

volume = "135",

pages = "269--273",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "4",

}

TY - JOUR

T1 - Concordance for clonal hematopoiesis is limited in elderly twins

AU - Fabre, Margarete Alice

AU - McKerrell, Thomas

AU - Zwiebel, Maximillian

AU - Vijayabaskar, M S

AU - Park, Naomi Rachel

AU - Wells, Philippa M

AU - Rad, Roland

AU - Deloukas, Panagiotis

AU - Small, Kerrin S

AU - Steves, Claire J

AU - Vassiliou, George S

PY - 2020/1/23

Y1 - 2020/1/23

N2 - Although acquisition of leukemia-associated somatic mutations by 1 or more hematopoietic stem cells is inevitable with advancing age, its consequences are highly variable, ranging from clinically silent clonal hematopoiesis (CH) to leukemic progression. To investigate the influence of heritable factors on CH, we performed deep targeted sequencing of blood DNA from 52 monozygotic (MZ) and 27 dizygotic (DZ) twin pairs (aged 70-99 years). Using this highly sensitive approach, we identified CH (variant allele frequency ≥0.5%) in 62% of individuals. We did not observe higher concordance for CH within MZ twin pairs as compared with that within DZ twin pairs, or to that expected by chance. However, we did identify 2 MZ pairs in which both twins harbored identical rare somatic mutations, suggesting a shared cell of origin. Finally, in 3 MZ twin pairs harboring mutations in the same driver genes, serial blood samples taken 4 to 5 years apart showed substantial twin-to-twin variability in clonal trajectories. Our findings propose that the inherited genome does not exert a dominant influence on the behavior of adult CH and provide evidence that CH mutations may be acquired in utero.

AB - Although acquisition of leukemia-associated somatic mutations by 1 or more hematopoietic stem cells is inevitable with advancing age, its consequences are highly variable, ranging from clinically silent clonal hematopoiesis (CH) to leukemic progression. To investigate the influence of heritable factors on CH, we performed deep targeted sequencing of blood DNA from 52 monozygotic (MZ) and 27 dizygotic (DZ) twin pairs (aged 70-99 years). Using this highly sensitive approach, we identified CH (variant allele frequency ≥0.5%) in 62% of individuals. We did not observe higher concordance for CH within MZ twin pairs as compared with that within DZ twin pairs, or to that expected by chance. However, we did identify 2 MZ pairs in which both twins harbored identical rare somatic mutations, suggesting a shared cell of origin. Finally, in 3 MZ twin pairs harboring mutations in the same driver genes, serial blood samples taken 4 to 5 years apart showed substantial twin-to-twin variability in clonal trajectories. Our findings propose that the inherited genome does not exert a dominant influence on the behavior of adult CH and provide evidence that CH mutations may be acquired in utero.

UR - http://www.scopus.com/inward/record.url?scp=85078379391&partnerID=8YFLogxK

U2 - 10.1182/blood.2019001807

DO - 10.1182/blood.2019001807

M3 - Article

C2 - 31697828

SN - 0006-4971

VL - 135

SP - 269

EP - 273

JO - Blood

JF - Blood

IS - 4

ER -

Concordance for clonal hematopoiesis is limited in elderly twins

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this