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Title: Prediction of acute myeloid leukaemia risk in healthy individuals
Author: Abelson, Sagi
Collord, Grace
Ng, Stanley W. K.
Weissbrod, Omer
Cohen, Netta Mendelson
Niemeyer, Elisabeth
Barda, Noam
Zuzarte, Philip C.
Heisler, Lawrence
Sundaravadanam, Yogi
Luben, Robert
Hayat, Shabina
Wang, Ting Ting
Zhao, Zhen
Cirlan, Iulia
Pugh, Trevor J.
Soave, David
Ng, Karen
Latimer, Calli
Hardy, Claire
Raine, Keiran
Jones, David
Hoult, Diana
Britten, Abigail
McPherson, John D.
Johansson, Mattias
Mbabaali, Faridah
Eagles, Jenna
Millers, Jessica K.
Pasternack, Danielle
Timms, Lee
Krzyzanowski, Paul
Awadalla, Philip
Costa, Rui
Segal, Eran
Bratman, Scott V.
Beer, Philip
Behjati, Sam
Martincorena, Inigo
Wang, Jean C. Y.
Bowles, Kristian M.
Quirós, J. Ramón
Karakatsani, Anna
Vecchia, Carlo La
Trichopoulou, Antonia
Salamanca Fernández, Elena
Huerta Castaño, José María
Barricarte, Aurelio
Travis, Ruth C.
Tumino, Rosario
Masala, Giovanna
Boeing, Heiner
Panico, Salvatore
Kaaks, Rudolf
Krämer, Alwin
Sieri, Sabina
Riboli, Elio
Vineis, Paolo
Foll, Matthieu
McKay, James D.
Polidoro, Silvia
Sala Serra, Núria
Khaw, Kay-Tee
Vermeulen, Roel
Campbell, Peter J.
Papaemmanuil, Elli
Minden, Mark D.
Tanay, Amos
Balicer, Ran D.
Wareham, Nicholas J.
Gerstung, Moritz
Dick, John E.
Brennan, Paul
Vassiliou, George S.
Shlush, Liran I.
Keywords: Leucèmia mieloide
Myeloid leukemia
Issue Date: 19-Jul-2018
Publisher: Nature Publishing Group
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 failure(1). 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 expansion(2,3). 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.
Note: Reproducció del document publicat a:
It is part of: Nature, 2018, vol. 559, num. 7714, p. 400
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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