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Longitudinal sequencing of RUNX 1 familial platelet disorder: new insights into genetic mechanisms of transformation to myeloid malignancies
Author(s) -
Duarte Bruno K. L.,
YamagutiHayakawa Gabriela G.,
Medina Samuel S.,
Siqueira Lúcia H.,
Snetsinger Brooke,
Costa Fernando F.,
Rauh Michael J.,
Ozelo Margareth C.
Publication year - 2019
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.15990
Subject(s) - runx1 , myeloid , neuroblastoma ras viral oncogene homolog , haematopoiesis , myelodysplastic syndromes , platelet disorder , medicine , immunology , cebpa , somatic evolution in cancer , bone marrow , cancer research , oncology , biology , gene , genetics , cancer , mutation , stem cell , platelet , kras
Summary The mechanisms by which patients with RUNX 1 familial platelet disorder with propensity to myeloid malignancies ( FPDMM ) develop myeloid malignancies ( MM ) are not fully understood. We report the results of targeted next‐generation sequencing on three patients with RUNX 1 FPDMM who developed acute myeloid leukaemia or myelodysplastic syndromes ( AML / MDS ). DNA samples were collected from bone marrow, peripheral blood and buccal swabs at different time points. One patient had clonal haematopoiesis, represented by an SRSF 2 p.P95R variant, prior to his AML diagnosis, when he developed an additional NRAS p.G12D variant. His sister presented to us with MDS , with a TET 2 p.S471fs and identical NRAS p.G12D variant. The third patient, from another family, had an additional RUNX 1 p.R204X and an NFE 2 p.Q139fs variant at AML diagnosis. This constitutes the first report of NFE 2 variants in AML without extramedullary disease and NRAS variants in AML / MDS in the setting of FPDMM . A systematic review of the literature including our findings distinguishes two genetic landscapes at AML transformation from FPDMM characterized by either the presence or absence of somatic abnormalities in RUNX 1 with or without variants in genes usually associated with MM . Whether clonal haematopoiesis precedes transformation only in patients without somatic abnormalities in RUNX 1 needs further confirmation.