Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family
Anand Pathak,
Katja Seipel,
Alexander Pemov,
Ramita Dewan,
Christina Brown,
Sarangan Ravichandran,
Brian T. Luke,
Michael Malasky,
Shalabh Suman,
Meredith Yeager,
NCI DCEG Cancer Genomics Research Laboratory,
NCI DCEG Cancer Sequencing Working Group,
Richard A. Gatti,
Neil E. Caporaso,
John J. Mulvihill,
Lynn R. Goldin,
Thomas Pabst,
Mary L. McMaster,
Douglas R. Stewart
Affiliations
Anand Pathak
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Katja Seipel
Departments of Medical Oncology and Clinical Research, University Hospital and University of Berne, Switzerland
Alexander Pemov
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Ramita Dewan
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Christina Brown
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Sarangan Ravichandran
Advanced Biomedical Computing Center, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Brian T. Luke
Advanced Biomedical Computing Center, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Michael Malasky
Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA
Shalabh Suman
Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA
Meredith Yeager
Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA
NCI DCEG Cancer Genomics Research Laboratory
NCI DCEG Cancer Sequencing Working Group
Richard A. Gatti
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
Neil E. Caporaso
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
John J. Mulvihill
Department of Pediatrics, Section of Genetics, The University of Oklahoma College of Medicine, OK, USA
Lynn R. Goldin
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Thomas Pabst
Departments of Medical Oncology and Clinical Research, University Hospital and University of Berne, Switzerland
Mary L. McMaster
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Douglas R. Stewart
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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.
