AN INTEGRATIVE GENOMIC APPROACH TO EXAMINE MUTATIONS AND BIOLOGICAL PATHWAYS ASSOCIATED WITH HAEMATOLOGICAL MALIGNANCY DEVELOPMENT IN DDX41 MUTATED FAMILIES

Abstract

DEAD-Box helicase 41 (DDX41) is the most commonly reported familial haematological malignancy (HM) gene first reported in 2015. Mutated, it predisposes to both MDS/AML and lymphoma, with HM diagnosis age like that of sporadic malignancies. Individuals with DDX41 mutation or deficiency have generally poor outcome with no effective targeted therapies available. Biological function of DDX41 leading to HM predisposition is poorly understood making risk assessment for asymptomatic carriers difficult. In over 50% of reported affected DDX41 germline mutated individuals, acquired somatic mutations are commonly identified on the other DDX41 allele. Through an integrative combinatorial genomics approach of whole exome sequencing, leukemic panel sequencing and RNA-sequencing, we comprehensively assessed six independent DDX41 germline mutated families. Each family presented varying penetrance of HM with affected and unaffected carriers as well as wildtype individuals assessed. Blood and bone marrow samples were assessed for the identification of somatic alterations in leukaemia associated genes in both malignant and pre-leukemic states. Interestingly, in both affected and unaffected DDX41 germline mutation carriers a minimal fingerprint of acquired somatic alterations was observed, potentially indicating a mechanism of leukaemia development unique to DDX41 mutations. Analysis of RNA-seq data through splicing and gene expression analysis to elucidate biological pathways which may be altered in DDX41 malignancy progression is ongoing. This integrative genomic approach to evaluate both mutations and biological pathways affected in DDX41 mutated malignancies will provide biological insight facilitating an advancement in diagnosis, risk assessment, monitoring and personalised treatment.