Genetic Predisposition to Therapy-Related Myeloid Neoplasm By Rare, Deleterious Germline Variants in DNA Repair Pathway and Myeloid Driver Genes

In this study, we performed comprehensive germline and somatic mutation profiling in t-MN using next generation sequencing. Matched germline material was available for 62/194 (32%) patients. Mutation profiling was correlated with clinical features including family history in 194 patients enrolled in the South Australian MDS (SA-MDS) registry and Cleveland Clinic (CC). An in-house well established filtering pipeline was used for identification of somatic mutations. Only variants with Genome Aggregation Database (gnomAD) minor allele frequency (MAF) of ≤0.01% and variant allele frequency (VAF) of ≥35% were selected for further analysis of germline variants. Variants reported in in the Catalogue of Somatic Mutations in Cancer database and MDS/AML were excluded from further analysis. Variants reported pathogenic in Breast Cancer Information Core (BIC) database and Leiden Open Variation Database (LOVD) were retained. Other variants were included if truncating (nonsense, indels, splice alterations), CADD>20, or predicted deleterious by >4/6 scoring algorithms (GERP>4, PhyloP>2, SIFT, PolyPhen2, MutationTaster and FATHMM).Forty-one (21%) t-MN patients harbored 45 rare (MAF<0.001) and deleterious germline mutations in the Fanconi anaemia (FA) pathway and driver myeloid genes including frameshift indels and splice site alterations in BRCA1, BRCA2, FANCA, PALB2, RAD51, DDX41 and TP53 (Figure 1A-B). The highest number of FA germline variants were seen in BRCA1 and F...
Source: Blood - Category: Hematology Authors: Tags: 636. Myelodysplastic Syndromes-Basic and Translational Studies: Poster I Source Type: research