139. Feasibility of comprehensive whole genome profiling in hematological malignancies

Aly Abdelkareem

Cinthya Zepeda Mendoza

I have a broad background in genomic sciences, with specific training in bioinformatics and human genetics. As a graduate student at Cold Spring Harbor Laboratories, I carried out molecular research on the structure of chromatin upon occurrence of copy-number variation. The intricate relationship between genome structure and function prompted me to pursue the study of human genomic disorders. As a postdoctoral fellow at Brigham and Women’s Hospital and Harvard Medical School I laid the groundwork for the development of computational tools to aid in the identification of position effects for balanced chromosome rearrangements. This analysis provided answers for the etiology of disease of various individuals enrolled in the Developmental Genome Anatomy Project, of which I had the pleasure of being part of. I took this experience to the clinic by joining the Laboratory Genetics and Genomics fellowship from Mayo Clinic, where I focused in the analysis of complex chromosome rearrangements associated with congenital diseases, structural variation in hematological malignancies (with a focus on B-ALL), and the study of molecular signatures of adult diffuse gliomas. I am currently a Senior Associate Consultant at Mayo Clinic. At Mayo Clinic, I have continued with my interests in human disease research, their diagnosis, and most importantly, the education of fellows and residents. It is my hope that my academic career and research path helps others find their own!

Abstract

Cinthya Zepeda Mendozaa, Anatasia Kellogga, Ashini Boliaa, Brendan O’Fallona, Philippe Szankasia, Luobin Yanga, Paul Rindlera, Eric Fredricksona, Devin Closea, Jay Patela, Xinjie Xub

aARUP Laboratories, Salt Lake City, UT, USA; bMayo Clinic, Rochester, MN, USA

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.