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Prediction of acute myeloid leukaemia risk in healthy individuals

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Title: Prediction of acute myeloid leukaemia risk in healthy individuals
Authors: Abelson, S
Collord, G
Ng, SWK
Weissbrod, O
Mendelson Cohen, N
Niemeyer, E
Barda, N
Zuzarte, PC
Heisler, L
Sundaravadanam, Y
Luben, R
Hayat, S
Wang, TT
Zhao, Z
Cirlan, I
Pugh, TJ
Soave, D
Ng, K
Latimer, C
Hardy, C
Raine, K
Jones, D
Hoult, D
Britten, A
McPherson, JD
Johansson, M
Mbabaali, F
Eagles, J
Miller, JK
Pasternack, D
Timms, L
Krzyzanowski, P
Awadalla, P
Costa, R
Segal, E
Bratman, SV
Beer, P
Behjati, S
Martincorena, I
Wang, JCY
Bowles, KM
Quirós, JR
Karakatsani, A
La Vecchia, C
Trichopoulou, A
Salamanca-Fernández, E
Huerta, JM
Barricarte, A
Travis, RC
Tumino, R
Masala, G
Boeing, H
Panico, S
Kaaks, R
Krämer, A
Sieri, S
Riboli, E
Vineis, P
Foll, M
McKay, J
Polidoro, S
Sala, N
Khaw, K-T
Vermeulen, R
Campbell, PJ
Papaemmanuil, E
Minden, MD
Tanay, A
Balicer, RD
Wareham, NJ
Gerstung, M
Dick, JE
Brennan, P
Vassiliou, GS
Shlush, LI
Item Type: Journal Article
Abstract: The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4-8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.
Issue Date: 19-Jul-2018
Date of Acceptance: 3-May-2018
URI: http://hdl.handle.net/10044/1/60874
DOI: https://doi.org/10.1038/s41586-018-0317-6
ISSN: 0028-0836
Publisher: Nature Publishing Group
Start Page: 400
End Page: 404
Journal / Book Title: Nature
Volume: 559
Copyright Statement: © 2018 Springer Nature Limited. All rights reserved. The final publication is available at Springer via https://doi.org/10.1038/s41586-018-0317-6
Sponsor/Funder: Italian Institute for Genomic Medicine IIGM
Funder's Grant Number: CG/150
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
CLONAL HEMATOPOIESIS
SOMATIC MUTATIONS
CANCER
MODELS
CLASSIFICATION
EVOLUTION
PATTERNS
Adult
Age Factors
Aged
Disease Progression
Electronic Health Records
Female
Genetic Predisposition to Disease
Health
Humans
Leukemia, Myeloid, Acute
Male
Middle Aged
Models, Genetic
Mutagenesis
Mutation
Prevalence
Risk Assessment
Humans
Disease Progression
Genetic Predisposition to Disease
Prevalence
Risk Assessment
Age Factors
Mutagenesis
Mutation
Models, Genetic
Adult
Aged
Middle Aged
Health
Female
Male
Leukemia, Myeloid, Acute
Electronic Health Records
MD Multidisciplinary
General Science & Technology
Publication Status: Published
Conference Place: England
Online Publication Date: 2018-07-09
Appears in Collections:School of Public Health



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