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http://hdl.handle.net/2445/172439
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 Mortalitat Myeloid leukemia Mortality |
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: https://doi.org/10.1038/s41586-018-0317-6 |
It is part of: | Nature, 2018, vol. 559, num. 7714, p. 400 |
URI: | http://hdl.handle.net/2445/172439 |
Related resource: | https://doi.org/10.1038/s41586-018-0317-6 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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AbelsonS.pdf | 4.75 MB | Adobe PDF | View/Open |
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