Patterns of somatic genome rearrangement in human cancer
type: CreativeWork
description: Cancer development is driven by somatic genome alterations, ranging from single point mutations to larger structural variants (SV) affecting kilobases to megabases of one or more chromosomes. Studies of somatic rearrangement have previously been limited by a paucity of whole genome sequencing data, and a lack of methods for comprehensive structural classification and downstream analysis. The ICGC project on the Pan-Cancer Analysis of Whole Genomes provides an unprecedented opportunity to analyse somatic SVs at base-pair resolution in more than 2500 samples from 30 common cancer types. In this thesis, I build on a recently developed SV classification pipeline to present a census of rearrangement across the pan-cancer cohort, including chromoplexy, replicative two-jumps, and templated insertions connecting as many as eight distant loci. By identifying the precise structure of individual breakpoint junctions and separating out complex clusters, the classification scheme empowers detailed exploration of all simple SV properties and signatures. After illustrating the various SV classes and their frequency across cancer types and samples, Chapter 2 focuses on structural properties including event size and breakpoint homology. Then, in Chapter 3, I consider the SV distribution across the genome, and show patterns of association with various genome properties. Upon examination of rearrangement hotspot loci, I describe tissue-specific fragile site deletion patterns, and a variety of SV profiles around known cancer genes, including recurrent templated insertion cycles affecting TERT and RB1. Turning to co-occurring alteration patterns, Chapter 4 introduces the Hierarchical Dirichlet Process as a non-parametric Bayesian model of mutational signatures. After developing methods for consensus signature extraction, I detour to the domain of single nucleotide variants to test the HDP method on real and simulated data, and to illustrate its utility for simultaneous signature discove…
abstract: Cancer development is driven by somatic genome alterations, ranging from single point mutations to larger structural variants (SV) affecting kilobases to megabases of one or more chromosomes. Studies of somatic rearrangement have previously been limited by a paucity of whole genome sequencing data, and a lack of methods for comprehensive structural classification and downstream analysis. The ICGC project on the Pan-Cancer Analysis of Whole Genomes provides an unprecedented opportunity to analyse somatic SVs at base-pair resolution in more than 2500 samples from 30 common cancer types. In this thesis, I build on a recently developed SV classification pipeline to present a census of rearrangement across the pan-cancer cohort, including chromoplexy, replicative two-jumps, and templated insertions connecting as many as eight distant loci. By identifying the precise structure of individual breakpoint junctions and separating out complex clusters, the classification scheme empowers detailed exploration of all simple SV properties and signatures. After illustrating the various SV classes and their frequency across cancer types and samples, Chapter 2 focuses on structural properties including event size and breakpoint homology. Then, in Chapter 3, I consider the SV distribution across the genome, and show patterns of association with various genome properties. Upon examination of rearrangement hotspot loci, I describe tissue-specific fragile site deletion patterns, and a variety of SV profiles around known cancer genes, including recurrent templated insertion cycles affecting TERT and RB1. Turning to co-occurring alteration patterns, Chapter 4 introduces the Hierarchical Dirichlet Process as a non-parametric Bayesian model of mutational signatures. After developing methods for consensus signature extraction, I detour to the domain of single nucleotide variants to test the HDP method on real and simulated data, and to illustrate its utility for simultaneous signature discove…
author: Roberts, Nicola Diane
language: en
keywords: cancer, genome, genomics, cancer genomics, structural variation, genome rearrangement, bioinformatics, pan-cancer analysis, hierarchical dirichlet process, mutational signatures
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/27b9961f-d78f-4a46-b203-1ebef26cb9c6/download
license: https://creativecommons.org/licenses/by-nc-nd/4.0/
date published: 2018-05-19
date modified: 2026-07-22T22:24:27Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.22674