Developing an Original Proteogenomic Atlas of Acute Myeloid Leukaemia in Nigerian Patients: Integration of Whole Genome Sequencing, Proteomics, and Clinical Phenotypes

This dissertation develops an original proteogenomic atlas of acute myeloid leukaemia (AML) in Nigerian patients by integrating whole genome sequencing, tandem mass spectrometry-based proteomics, and clinical phenotyping, providing the first comprehensive molecular characterisation of AML in a West African population and identifying Nigeria-specific disease features with therapeutic implications. AML molecular classification in Nigeria relies on morphology and immunophenotyping without systematic genomic characterisation, resulting in treatment decisions based on data from populations with substantially different AML genetic landscapes. Bone marrow aspirate and peripheral blood samples from 100 newly diagnosed AML patients at Lagos University Teaching Hospital, University College Hospital Ibadan, and Ahmadu Bello University Teaching Hospital were collected. Whole genome sequencing was performed at 30x coverage. Tandem mass tag-based proteomics quantified 7,200 proteins from leukemic blasts. Clinical data including treatment response at day 30, remission rates, and 12-month survival were prospectively captured. CEBPA biallelic mutations were identified in 21 percent of patients, significantly higher than published European frequencies (7 to 12%), representing an original population-level finding. A novel recurrent in-frame deletion in the ETO domain of RUNX1T1 was identified in 8 percent of cases and is proposed as a Nigeria-specific driver mutation. Proteogenomic integration identified TYRO3 as a druggable kinase overexpressed in CEBPA-mutant AML. An original Nigerian AML Proteogenomic Classification with eight molecular subtypes is proposed, providing a framework for risk stratification. Keywords: acute myeloid leukaemia, proteogenomics, whole genome sequencing, Nigerian cancer, molecular classification.