title: Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival.
abstract: While most myelodysplastic syndrome/acute myeloid leukemia cases are sporadic, rare familial cases occur and provide some insight into leukemogenesis. The most clearly defined familial cases result from inherited mutations in RUNX1 or CEBPA. Recently, novel germline mutations in GATA2 have been reported. We, therefore, investigated individuals from families with one or more first-degree relatives with myelodysplastic syndrome/acute myeloid leukemia with wild-type RUNX1 and CEBPA, for GATA2 mutations. Screening for other recurrent mutations was also performed. A GATA2 p.Thr354Met mutation was observed in a pedigree in which 2 first-degree cousins developed high-risk myelodys-plastic syndrome with monosomy 7. They were also observed to have acquired identical somatic ASXL1 mutations and both died despite stem cell transplantation. These findings confirm that germline GATA2 mutations predispose to familial myelodysplastic syndrome/acute myeloid leukemia, and that monosomy 7 and ASXL1 mutations may be recurrent secondary genetic abnormalities triggering overt malignancy in these families.
authors.affiliation: Centre of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Csaba
authors.initials: C
authors.lastname: Bödör
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.forename: Matthew
authors.initials: M
authors.lastname: Smith
authors.forename: Aurélie
authors.initials: A
authors.lastname: Charazac
authors.forename: Sameena
authors.initials: S
authors.lastname: Iqbal
authors.forename: Pascaline
authors.initials: P
authors.lastname: Etancelin
authors.forename: Jamie
authors.initials: J
authors.lastname: Cavenagh
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Barnett
authors.forename: Karolina
authors.initials: K
authors.lastname: Kramarzová
authors.forename: Biju
authors.initials: B
authors.lastname: Krishnan
authors.forename: András
authors.initials: A
authors.lastname: Matolcsy
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: Jude
authors.initials: J
authors.lastname: Fitzgibbon
authors.forename: Carolyn
authors.initials: C
authors.lastname: Owen
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001483:Base Sequence; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D050989:GATA2 Transcription Factor / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000401:mortality; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics*; D015996:Survival Rate
chemical_list: C473949:ASXL1 protein, human; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D012097:Repressor Proteins