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https://hdl.handle.net/2440/124534
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Type: | Journal article |
Title: | RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML |
Author: | Brown, A.L. Arts, P. Carmichael, C.L. Babic, M. Dobbins, J. Chong, C.-E. Schreiber, A.W. Feng, J. Phillips, K. Wang, P.P.S. Ha, T. Homan, C.C. King-Smith, S.L. Rawlings, L. Vakulin, C. Dubowsky, A. Burdett, J. Moore, S. McKavanagh, G. Henry, D. et al. |
Citation: | Blood Advances, 2020; 4(6):1131-1144 |
Publisher: | American Society of Hematology |
Issue Date: | 2020 |
ISSN: | 2473-9529 2473-9537 |
Statement of Responsibility: | Anna L. Brown … Andreas W. Schreiber … Claire C. Homan … Richard J. D’Andrea, Ian D. Lewis, Devendra K. Hiwase … Nicola K. Poplawski, Christopher N. Hahn, Hamish S. Scott … et al. |
Abstract: | First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM. |
Keywords: | Germ Cells Humans Pedigree Epigenesis, Genetic Phenotype Mutation Core Binding Factor Alpha 2 Subunit Leukemia, Myeloid, Acute |
Rights: | © 2020 by The American Society of Hematology |
DOI: | 10.1182/bloodadvances.2019000901 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1145278 http://purl.org/au-research/grants/nhmrc/1164601 http://purl.org/au-research/grants/nhmrc/1023059 http://purl.org/au-research/grants/nhmrc/1125849 |
Published version: | http://dx.doi.org/10.1182/bloodadvances.2019000901 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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