"CHEK2 mutations as predisposition alleles for inherited hematopoietic malignancies"
Lucy A. Godley, MD. PhD
Professor, Department of Medicine, University of Chicago
2016 Fletcher Scholar - 2017 Interim Report
CHEK2 mutations as predisposition alleles for inherited hematopoietic malignancies
The overall goal of this award is to test the hypothesis that inherited mutations of CHEK2 confer risk for the blood and bone marrow cancers. We have been working on experiments that test this hypothesis, organized in two Aims:
(1) To determine if additional genetic alterations exist in patients with familial CHEK2 mutations who have bone marrow-derived cancers; and
(2) To generate a mouse model that mimics the CHEK2 mutation seen most frequently in these families.
Progress to date:
Aim 1: To determine if additional genetic alterations exist in patients with familial CHEK2 mutations who have bone marrow-derived cancers.
Eight samples of patients with hematopoietic malignancies and the CHEK2 I157T variant have undergone whole genome sequencing (WGS). We have established a bioinformatic pipeline to call variants in these samples, and we are currently organizing the called variants into Data Levels according to the recommendations of the American College of Human Genetics. Importantly, our bioinformatic pipeline calls the CHEK2 I157T variant (rs17879961) in all samples. Also, of great medical significance for two families, we have identified actionable mutations in two genes (one each in two independent families) that have clinical implications. Once we have collated all of the variants, we will offer this research level information to patients. If they choose to receive the information, we will counsel them as to how to obtain clinical confirmation of the detected actionable mutations. We will use this WGS data in two ways:
(i) we will estimate the population admixtures of each sample and will use those estimates to determine if the CHEK2 I157T variant is overrepresented in patients with hematopoietic malignancies; and
(ii) we will determine if any variant co-segregates with the CHEK2 I157T variant, suggesting a cooperative effect.
Aim 2: To generate a mouse model that mimics the CHEK2 mutation seen most frequently in these families.
The University of Chicago Transgenic Mouse and Embryonic Stem Cell Facility has generated a targeting construct that should direct the expression of the homologous Chek2 murine amino acid, I161T. The Godley Laboratory has confirmed the correct sequence of the construct. The next steps to be performed include generation of the targeting fragment and electroporation of the fragment into mouse ES cells from the C57Bl/6 mouse strain. We anticipate that mice expressing Chek2I161T will be available for studies by December 2017.
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