Clinical Utility and Impact of Targeted Nucleic Acid Sequencing in Myeloid Malignancies and Precursor Lesions

dc.contributor.authorFerrone, Christinaen
dc.contributor.departmentPathology and Molecular Medicineen
dc.contributor.supervisorRauh, Michael's University at Kingstonen
dc.description.abstractRecent technological advances have permitted the identification of several genes recurrently mutated in myeloid malignancies, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML), with expanding diagnostic and clinical significance. Given the breadth of genetic aberrations required to diagnose these diseases, higher throughput testing is necessary. Targeted next-generation sequencing (NGS) panels offer promise in detecting these molecular features. Furthermore, several myeloid precursor lesions, such as clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenias of undetermined significance (CCUS), have been linked to the development of myeloid malignancies. We propose that universal implementation of NGS in cases of suspicious or confirmed myeloid malignancy will improve diagnostics, prognostics, and inform management decisions for patients with myeloid disease. Herein, we present our validation of the targeted Oncomine Myeloid NGS panel (Thermo Fisher). We further compare commercial variant analysis workflows accompanying the panel with a custom analysis pipeline, demonstrating that supplementing commercial filters with manual variant interpretation improves variant detection. We also performed prospective sequencing in patients with various myeloid malignancies, demonstrating that variants identified through molecular profiling can inform patient care. Additionally, we found that the detection of even a single variant, versus 0 variants, was independently predictive of overall survival. Furthermore, retrospective NGS of a cohort of individuals with suspicious or confirmed myeloid neoplasms (MN) with myelodysplasia facilitated the diagnosis of all suspicious cases as either MN or idiopathic cytopenia of undetermined significance (ICUS) or CCUS; the latter of which would otherwise have remained undiagnosed. We further assessed evolution of these precursor lesions to myeloid disease via serial sequencing. Our findings demonstrate the similarity of CCUS and low-risk MDS, supporting the proposal that CCUS should be classified accordingly in the next revision of the WHO guidelines. Finally, we present a case report of a single MDS patient, highlighting the value of serial sequencing in monitoring clonal evolution and disease progression, as well as the importance of comprehensive variant calling. Collectively, these findings highlight the importance of integrating NGS into routine clinical care for patients with idiopathic cytopenias and all types of myeloid malignancy.en
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
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dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
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dc.subjectMyeloid Malignancyen
dc.subjectClinical Utilityen
dc.titleClinical Utility and Impact of Targeted Nucleic Acid Sequencing in Myeloid Malignancies and Precursor Lesionsen
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