| Popis: |
Myeloid malignancies are rare but severe clonal disorders found in hematopoietic stem or progenitor cells. Both genetic and epigenetic changes can contribute to the disease by disturbing some key aspects in cells such as self-renewal, proliferation, and differentiation. Therefore, it is important to know which genes are associated with these diseases in order to increase our understanding assess disease risk and develop therapeutic strategies to treat the disease. Recurrent somatic mutations in some genes, such as RUNX1, IDH1/2 and FLT3, are known to be associated with development of these diseases. However, in finding the association between genes and myeloid malignancies, there is still a question as to the degree to which germline rare variants contribute to the disease phenotype.In chapter 3, we will present our findings from 690 myeloid malignancies patients’ whole-exome sequence data to elucidate the contribution to disease susceptibility of rare (< 1% population allele frequency) protein-altering alleles. We estimate that 3-4% of patients have rare variants in genes that would classify the patients as having germline predisposition under current guidelines. We also identify MPO as a new candidate predisposition gene, with 19 patients (2.8%) harboring rare pathogenic MPO variants and significantly higher pathogenic allele frequencies in cases as compared to population controls. An elevated rare-variant burden is observed in autosomal recessive genes, particularly Fanconi anemia (FA) genes. The proportion of rare variants that are truncating is substantially higher in autosomal recessive and FA genes than in other. Even after accounting for numbers of rare variants, inherited pairs of such variants in the same patient and same FA gene (presumably affecting both parental homologs) are observed at a rate significantly higher than would be expected by chance, suggesting biparental inheritance of rare alleles in FA genes as a risk factor for myeloid malignancy. The FA gene BRCA2 is particularly enriched for biparental inheritance, and rare germline BRCA2 variants are associated with poor overall survival. |
