Signaling Gene Mutations Are Characterized By Diverse Patterns of Expansion and Contraction during Progression from MDS to Secondary AML

• Published in: Blood 2020-11, Vol.136 (Supplement 1), p.2-3
• Main Authors: Menssen, Andrew J, Khanna, Ajay, Miller, Christopher A, Chang, Gue Su, Shao, Jin J, Nonavinkere Srivatsan, Sridhar, Robinson, Joshua, O'Laughlin, Michelle, Fronick, Catrina, Fulton, Robert, Brendel, Kimberly J, Heath, Sharon E, Westervelt, Peter, DiPersio, John F., Link, Daniel C., Jacoby, Meagan A., Duncavage, Eric, Ley, Timothy J, Walter, Matthew J.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2020-140394

Background: Previous studies indicate that mutations in signaling (e.g., receptor tyrosine kinases and RAS pathway members) and transcription factor genes are more common in secondary acute myeloid leukemia (sAML) than myelodysplastic syndrome (MDS), suggesting a role in disease progression. However, our understanding of the timing and order of mutation acquisition in these genes remains incomplete without analyzing paired MDS and sAML samples from the same patient. Defining the role of signaling gene mutations during progression should provide biologic insight into clonal evolution and help define prognostic markers for MDS progression. Methods: We banked paired MDS and sAML (and matched skin) samples from 44 patients (median time to progression: 306 days, range 21-3568). We sequenced 44 sAML (+ skin) samples for 285 recurrently mutated genes (RMGs) and 12 samples were selected for enhanced whole genome sequencing (eWGS, genome with deep exome coverage) of MDS and sAML samples (+ skin) to determine clonal hierarchy. Somatic mutations in these 12 samples were validated with high coverage error-corrected sequencing, and clonality was defined in MDS and sAML samples using mutation variant allele frequencies (VAFs). Additionally, error-corrected sequencing for all sAML RMG mutations, plus 40 additional genes, was performed on 43 of the MDS samples. Single cell DNA sequencing (scDNAseq, Mission Bio) was performed on 6 samples. Results: We identified 32 signaling gene mutations in 15 of the 44 sAML samples, with only 11 of 32 mutations (34%) detected in the initial, paired MDS sample (limit of detection;