ASPO Abstracts
Genome-wide association and inference of clonal mosaicism implicates germline variation as a driver of genome instability
Category: Molecular Epidemiology & Environment, Early Detection & Risk Prediction
Conference Year: 2018
Abstract Body:
Errors in DNA replication and cell division create daughter cells with chromosomal aberrations that propagate to establish genetically distinct cell populations within an individual. This phenomenon, known as clonal mosaicism, is positively correlated with age and is an important factor in the development of cancer. Blood mosaicism is a strong prognostic marker for hematological cancers. Germline variation is associated with the rare mosaic variegated aneuploidy syndrome. However, the role of less penetrant genetic variants in mosaicism of healthy tissue has not been established. This is due, in part, to critical difficulties in phenotyping. Here we sought to overcome this challenge by conducting a genome-wide association study of clonal mosaicism in samples that were characterized by a haplotype based method to obtain high-fidelity phenotyping of mosaicism. Our analysis included 4 studies from the GENEVA consortium comprised of 9,115 individuals, of which 295 exhibited detectable mosaicism. Meta-analysis following standard imputation-based techniques revealed significant association with mosaicism at two loci, 13q32.2 (P < 1e-8, OR = 1.6) and 10p14 (P < 4.6e-8, OR = 2.1). Genome-wide significant hits include three intronic FARP1 SNPs and one intronic SFMBT2 SNP. FARP1 gene expression is prognostic in renal cancer. In addition, four loci exhibited suggestive evidence for association (P < 5e-7). One of these SNPs is 52kb upstream of XPO1 which regulates nuclear export of RNA and proteins involved in cell cycle regulation, including P53. XPO1 is overactive in many cancers and recent studies suggest that XPO1 inhibitors have anti-tumor activity in patients with hematological malignancies. A second marginally significant hit is 4kb from ADAR1, a gene that is required for normal hematopoiesis and that promotes malignant progenitor reprogramming in chronic myeloid leukemia. In our study, SNPs associated with hematological cancers (GWAS catalog) showed inflated p-values. In summary, we have identified inherited forms of genetic variation that potentially explain the development of detectable clonal mosaicism, an established prognostic factor in hematological malignancy, which may offer insights into the etiology of cancer, early detection and prevention.
Keywords: mosaicism hematological cancer GWAS