title: Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family.
abstract: Familial acute myeloid leukemia is rare and linked to germline mutations in RUNX1, GATA2 or CCAAT/enhancer binding protein-α (CEBPA). We re-evaluated a large family with acute myeloid leukemia originally seen at NIH in 1969. We used whole exome sequencing to study this family, and conducted in silico bioinformatics analysis, protein structural modeling and laboratory experiments to assess the impact of the identified CEBPA Q311P mutation. Unlike most previously identified germline mutations in CEBPA, which were N-terminal frameshift mutations, we identified a novel Q311P variant that was located in the C-terminal bZip domain of C/EBPα. Protein structural modeling suggested that the Q311P mutation alters the ability of the CEBPA dimer to bind DNA. Electrophoretic mobility shift assays showed that the Q311P mu-tant had attenuated binding to DNA, as predicted by the protein modeling. Consistent with these findings, we found that the Q311P mutation has reduced transactivation, consistent with a loss-of-function mutation. From 45 years of follow up, we observed incomplete penetrance (46%) of CEBPA Q311P. This study of a large multi-generational pedigree reveals that a germline mutation in the C-terminal bZip domain can alter the ability of C/EBP-α to bind DNA and reduces transactivation, leading to acute myeloid leukemia.
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Pathak
authors.affiliation: Departments of Medical Oncology and Clinical Research, University Hospital and University of Berne, Switzerland.
authors.forename: Katja
authors.initials: K
authors.lastname: Seipel
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pemov
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ramita
authors.initials: R
authors.lastname: Dewan
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Brown
authors.affiliation: Advanced Biomedical Computing Center, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Sarangan
authors.initials: S
authors.lastname: Ravichandran
authors.affiliation: Advanced Biomedical Computing Center, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Luke
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Malasky
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.
authors.forename: Shalabh
authors.initials: S
authors.lastname: Suman
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Department of Human Genetics, David Geffen UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gatti
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Caporaso
authors.affiliation: Department of Pediatrics, Section of Genetics, The University of Oklahoma College of Medicine, OK, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mulvihill
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lynn R
authors.initials: LR
authors.lastname: Goldin
authors.affiliation: Departments of Medical Oncology and Clinical Research, University Hospital and University of Berne, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: McMaster
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA drstewart@mail.nih.gov.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Stewart
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005190:Family; D005260:Female; D005500:Follow-Up Studies; D015973:Gene Expression Regulation, Leukemic; D005838:Genotype; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D010375:Pedigree; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055815:Young Adult
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha