In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2756-2756
Abstract:
Familial acute myeloid leukemia (AML) is rare and linked to germline mutations in RUNX1 or CCAAT/enhancer binding protein-α (CEBPA). We conducted whole-exome sequencing on a large family with AML originally evaluated at NIH in 1969 and uncovered a CEBPA Q311P mutation in all tested, affected members. The Q311P variant, located in the C-terminal bZip domain of CEBPA, was predicted to be highly deleterious by in silico algorithms; the Q311 position was highly conserved among CEBPA orthologs and paralogs. This variant has not been observed in the NHLBI's Exome Sequencing Project or the Broad Institute's Exome Aggregation Consortium. 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 mutant had attenuated binding to DNA, as predicted by the protein modeling. Consistent with these findings, we found that the Q311P mutation has reduced transactivation of a promoter with a tetramer of CEBP sites, consistent with a loss-of-function mutation. In addition, there was decreased colony survival in fibroblasts with CEBPA Q311P, associated with the clinical radiosensitivity postulated in one carrier. From 45 years of follow-up, we observed incomplete penetrance (46%) of CEBPA Q311P; we did not observe other cancers or leukemias segregating with the mutation. Thus, we present a comprehensive clinical and molecular characterization of a novel AML-associated variant in CEBPA in a NCI family with nearly half a century of follow-up. This study reveals that a germline mutation in the C-terminal bZip domain can alter the ability of CEBPA to bind DNA and reduces transactivation, leading to AML, though with lower penetrance than the canonical N-terminal frameshift germline mutations. Citation Format: Anand Pathak, Katja Seipel, Alexander Pemov, Ramita Dewan, Christina Brown, Sarangan Ravichandran, Brian T. Luke, Meredith Yeager, Richard A. Gatti, Neil Caporaso, John J. Mulvihill, Lynn Goldin, Thomas Muller Pabst, Mary Lou McMaster, Douglas R. Stewart. Whole-exome sequencing reveals a novel germline variant in CEBPA-associated familial acute myeloid leukemia: 45-year follow-up of a large family. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2756. doi:10.1158/1538-7445.AM2015-2756
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-2756
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
