How Morphologic Features Are Shaped By Underlying Somatic Genotype in MDS

Morphology has been the pillars of the MDS diagnosis. In the genetic era, the subjectivity of pathologic evaluation in the absence of integration with mechanistic correlations is a clear limitation of current diagnostic schemes. Well-known genotype/phenotype associations, including e.g., linking of SF3B1 mutations to RARS or JAK2/SF3B1 mutations to RARS-T, suggest that somatic events can shape morphologic features and vice versa. However, the complexity of morphologic and genetic changes precludes identification of many consequential genotype/phenotype associations. As objective image analytic tools are being developed, this project aims at determining the most mutually predictive relationships between combinations of morphologic features and genomic changes. We have analyzed 1,079 MDS patients for somatic CNVs and mutations in a targeted panel of 33 genes frequently mutated in myeloid cancers. Our stringent bioanalytic pipeline removed artifacts, SNPs and errors. We applied this pipeline to discovery (2/3) and validation (1/3) cohorts. Bone marrow morphological alterations were mapped to binary features called by an independent pathologist in a blinded fashion based on uniformly defined criteria occurring in >10% of cells. A total of 10 such features were investigated. For instance, myeloid, erythroid and megakaryocytic dysplasia occurred in 54%, 70% and 72% of patients, respectively. 89% had at least one cytopenia, 57% multiple cytopenias, and 50% had at least one myeloproliferative feature (e.g., monocytosis). In addition, all cases were partitioned in accordance with two risk groups defined by IPSS-R (lower risk 3.5). NGS analysis identified 1,929 somatic mutations, but for proper correlation with morphologic definitions only mutations with a clonal burden >10% were used. Our initial univariate analysis yielded 52 significant associations (q Download : Download high-res image (234KB) Download : Download full-size image Disclosures Nazha: Jazz Pharmacutical: Research Funding; Abbvie: Consultancy; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Daiichi Sankyo: Consultancy; Tolero, Karyopharma: Honoraria; Incyte: Speakers Bureau. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Hobbs: Amgen: Research Funding; SimulStat Inc.: Consultancy. Maciejewski: Novartis: Consultancy; Alexion: Consultancy.