139. Feasibility of comprehensive whole genome profiling in hematological malignancies

Abstract

Whole genome sequencing (WGS) has been recently proposed as a replacement for routine karyotype and FISH analyses of myeloid and lymphoid neoplasms. WGS allows for the unbiased and comprehensive detection of multiple types of genomic aberrations, from single nucleotide to structural variants, which could streamline current genomic testing algorithms and clinical laboratory workflows for hematologic malignancies. In this study, we explored the feasibility of whole genome profiling of myeloid and lymphoid neoplasms by sequencing eleven AML, MPN, MDS, B-ALL, and T-ALL genomes with an average depth of sequencing coverage of ∼40X, and comparing genome analyses data to their available cytogenetic and molecular panel results. 81% of clinically relevant SNVs were detected by WGS, with false negatives being mostly variants at low frequencies (VAF <10%). Nine new variants were detected by WGS in an AML, B-ALL and T-ALL samples, eight of which were classified as VUS, and one (FLT3 p.Tyr572Cys) in B-ALL as likely pathogenic. 95% of clinically relevant copy-number variants (CNVs) were detected by WGS, with false negatives being mostly small (<150Kb) or mosaic CNVs present in <15% of the sample. The identification of the clinically relevant translocations in these samples (such as ETV6/RUNX1 and CRLF2 rearrangements) using WGS data is currently being investigated. This feasibility study demonstrated the potential of using WGS as the replacement of molecular panels and chromosome microarray in hematologic malignancies, particularly at the time of initial diagnosis.