RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML.

Autor:	Brown AL; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.; School of Medicine, University of Adelaide, Adelaide, SA, Australia., Arts P; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., Carmichael CL; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Babic M; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., Dobbins J; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., Chong CE; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Schreiber AW; School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.; Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia., Feng J; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.; Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia., Phillips K; Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia., Wang PPS; Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia., Ha T; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., Homan CC; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., King-Smith SL; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., Rawlings L; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Vakulin C; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Dubowsky A; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Burdett J; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Moore S; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., McKavanagh G; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Henry D; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Wells A; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Mercorella B; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Nicola M; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Suttle J; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Wilkins E; Department of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Li XC; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., Michaud J; Department of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Brautigan P; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., Cannon P; Department of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Altree M; Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia., Jaensch L; Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia., Fine M; Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia., Butcher C; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.; Department of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, SA, Australia., D'Andrea RJ; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., Lewis ID; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.; Department of Haematology, SA Pathology, Adelaide, SA, Australia., Hiwase DK; School of Medicine, University of Adelaide, Adelaide, SA, Australia.; Department of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, SA, Australia.; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia., Papaemmanuil E; Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY., Horwitz MS; Department of Pathology, University of Washington, Seattle, WA., Natsoulis G; Imago Biosciences, Inc, San Francisco, CA., Rienhoff HY; Imago Biosciences, Inc, San Francisco, CA., Patton N; Department of Haematology, Auckland City Hospital, Auckland, New Zealand., Mapp S; Department of Haematology, Princess Alexandra Hospital, Brisbane, QLD, Australia., Susman R; Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia., Morgan S; Department of Haematology, Alfred Hospital, Melbourne, VIC, Australia., Cooney J; Department of Haematology, Fiona Stanley Hospital, Murdoch, WA, Australia., Currie M; LewisGale Medical Center, Salem, VA., Popat U; The University of Texas MD Anderson Cancer Center, Houston, TX., Bochtler T; Clinical Cooperation Unit Molecular Hematology/Oncology, Department of Internal Medicine V, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany., Izraeli S; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.; Pediatric Hemato-Oncology, Schneider Children's Medical Center, Petach Tiqva, Israel., Bradstock K; Haematology Department, Westmead Hospital, Westmead, NSW, Australia., Godley LA; Section of Hematology/Oncology, Department of Medicine and Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL., Krämer A; Clinical Cooperation Unit Molecular Hematology/Oncology, Department of Internal Medicine V, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany., Fröhling S; National Center for Tumor Diseases Heidelberg, German Cancer Research Center, Heidelberg University Hospital, Heidelberg, Germany.; German Cancer Consortium, Heidelberg, Germany., Wei AH; The Alfred Hospital, Monash University, Melbourne, VIC, Australia., Forsyth C; Jarrett St Specialist Centre, North Gosford, NSW, Australia; and., Mar Fan H; Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia., Poplawski NK; Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.; Discipline of Paediatrics, Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, SA, Australia., Hahn CN; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.; School of Medicine, University of Adelaide, Adelaide, SA, Australia., Scott HS; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.; School of Medicine, University of Adelaide, Adelaide, SA, Australia.; Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2020 Mar 24; Vol. 4 (6), pp. 1131-1144.
DOI:	10.1182/bloodadvances.2019000901
Abstrakt:	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. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
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