Abstract:
Elucidation and characterisation of germline disease-causing variants is essential to understand, diagnose and treat inherited disorders. This has proven very difficult for inherited blood cancers, due to their rarity, the small sizes of affected families, the often-low penetrance of the trait, and hence the complexity of the bioinformatics analysis to find candidate susceptibility gene variants. Consequently, the research and clinical utility of blood cancer genetics has been stalled, and only eleven blood cancer susceptibility genes have been confirmed. This study aimed to identify candidate blood cancer susceptibility gene variants in two cases where multiple blood cancers had developed, either within a single patient (Hodgkin Lymphoma (HL) and Acute Myeloid Leukaemia (AML) in Patient1) or within a single family (AML in two daughters from Family1). Eight bioinformatics programs were utilised (FastQC, BWA, SAMtools, Picard, VarScan2, ANNOVAR, snpEff and SnpSift), alongside scientific literature and online databases, to identify candidate variants. Whole-exome sequencing data was progressively filtered for all individuals, to retain variants that were rare, likely deleterious and found in high-interest genes. Additionally, it was investigated whether relevant variants were constitutional or acquired, and in Family1 germlinetransmission was assessed. The strongest Patient1 candidates were the novel MLLT10 c.2561G>A and previously reported PTPN22 c.1858T>C variants, where PTPN22 also had a somatic hit (c.473C>T). Respectively, these candidates were proposed to dysregulate gene expression and tyrosine phosphatase signalling to cause hyperproliferation and leukaemic transformation. In Family1, the two strongest candidates were germline-inherited for the living affected daughter only (MEN1 c.700C>T and NF1 c.528T>A). Respectively, these candidates were proposed to be leukaemogenic via dysregulated gene expression promoting differentiation during haematopoiesis, and via excessive Ras signalling to upregulate proliferation and survival. The somatic NF1 c.4168G>T and NRAS c.34G>A hits might also disrupt the Ras pathway. All candidate variants warrant validation through future research. This study was significant in implicating MLLT10, PTPN2 and MEN1 as novel potential blood cancer susceptibility genes, and in introducing a new NF1 candidate blood cancer susceptibility gene variant. Further, the bioinformatics protocols from this study could be significant in streamlining the future identification of susceptibility variants for cancers and other genetic disorders.
