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Computational methods for the detection of somatic structural variants in cancer genomes using long-read sequencing https://doi.org/10.17863/CAM.117082 Elrick, Hillary Cortes Ciriano, Isidro Accurate detection of somatic structural variants (SVs) is critical for informing the diagnosis and treatment of human cancers. In this thesis, I present SAVANA, a computational method for the analysis of somatic SVs using long-read whole genome sequencing data from tumours and matched normal samples. SAVANA employs machine learning to distinguish true somatic SVs from germline events and noise. Additionally, I establish best practices for benchmarking SV detection using simulated and sequencing replicates to demonstrate SAVANA’s superior sensitivity, specificity, and speed compared to existing methods. I show that SAVANA performs robustly across a variety of clonality levels, genomic regions, SV types, and sizes. Using Illumina and Oxford Nanopore whole-genome sequencing data from 99 tumours and matched normal samples of patients, I show that SVs reported by SAVANA are highly concordant with those detected using short-read sequencing, including in regions of complex structural variation. I also highlight the enhanced ability of long-reads to identify SVs in repetitive regions where short-reads are unable to map with high confidence. In summary, this thesis introduces SAVANA as a novel computational method to identify somatic SVs in long-reads, establishes a robust framework for benchmarking SV detection, and demonstrates the method’s high consistency and enhanced sensitivity compared to short-reads across a large patient cohort. University of Cambridge 2024-11-04 Thesis Doctoral Doctor of Philosophy (PhD) eng EMBL-EBI https://www.repository.cam.ac.uk/handle/1810/382098 embargo 2026-04-01 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/ad5c3fb0-7fd5-448c-8976-c7ddb25c9d51/download 5f64417b757699d7e5259fae68649a96 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/d323ee04-834f-446e-ad73-7ddada068fc2/download 87eda9de84448d1f82354d60eee3eb5f http://purl.org/NET/rdflicense/allrightsreserved bioinformatics cancer genomics long-read whole genome sequencing structural variants