Chromosomal instability (CIN), defined as the process of losing or gaining whole or parts of chromosomes, is one of the earliest molecular characteristics to be described in cancer. Since its detection by light microscopy in the late 19th century, technological advances have facilitated the observation of CIN at increasing resolution, revealing an extreme genomic complexity which we are only beginning to understand. As such, CIN has become a hallmark of cancer. Despite its major influence in cancer evolution, fundamental questions as to the frequency of CIN across human cancers, the number of detectable types in a genome, and the possibility of their co-occurrence, remain only partially answered.

In this thesis, I present a comprehensive compendium of CIN in cancer using genomic profiling of over 10,000 patient tumours. Firstly, I establish an empirical threshold to detect chromosomal instability which shows that 80% of all tumours have detectable levels of CIN. Secondly, I derive robust genomic signatures of 17 different types of CIN. I discover that chromosomal instability is overwhelmingly driven by two signatures: errors during mitosis through telomere attrition or chromosome missegregation, and non-mitotic errors via impaired homologous recombination. Analysing the co-occurrence of signatures, I find that the remaining signatures (except one) co-occur significantly more often with either one of these two signatures. These results reveal two dominant modes of CIN in human cancers.

To interrogate different types of CIN, I develop a triangulation-based framework by integrating diverse sets of genomic features from public data. This allows me to propose putative aetiologies underpinning the signatures and link them to the existing literature. Finally, I show that combinations of signatures distinguish complex genotypes, such as BRCA1 from BRCA2 germline mutant cancers, or sarcoma cancer subtypes known as one of the most karyotypically complex cancers.

The extensive complexity of highly unstable tumours has so far restricted the effectiveness of targeted therapies and improvements in patient survival. This thesis facilitates a deeper understanding of one of the most crucial hallmarks of cancer. My results illuminate the fundamental structure underlying genomic complexity, to guide future research efforts on mitosis and homologous recombination.