Unravelling the tumour genome: The evolutionary and clinical impacts of structural variants in tumourigenesis

Abstract

Structural variants (SVs) represent a major source of aberration in tumour genomes. Given the diversity in the size and type of SVs present in tumours, the accurate detection and interpretation of SVs in tumours is challenging. New classes of complex structural events in tumours are discovered frequently, and the definitions of the genomic consequences of complex events are constantly being refined. Detailed analyses of short-read whole-genome sequencing (WGS) data from large tumour cohorts facilitate the interrogation of SVs at orders of magnitude greater scale and depth. However, the inherent technical limitations of short-read WGS prevent us from accurately detecting and investigating the impact of all the SVs present in tumours. The expanded use of long-read WGS will be critical for improving the accuracy of SV detection, and in fully resolving complex SV events, both of which are crucial for determining the impact of SVs on tumour progression and clinical outcome. Despite the present limitations, we demonstrate that SVs play an important role in tumourigenesis. In particular, SVs contribute significantly to late-stage tumour development and to intratumoural heterogeneity. The evolutionary trajectories of SVs represent a window into the clonal dynamics in tumours, a comprehensive understanding of which will be vital for influencing patient outcomes in the future. Recent findings have highlighted many clinical applications of SVs in cancer, from early detection to biomarkers for treatment response and prognosis. As the methods to detect and interpret SVs improve, elucidating the full breadth of the complex SV landscape and determining how these events modulate tumour evolution will improve our understanding of cancer biology and our ability to capitalise on the utility of SVs in the clinical management of cancer patients.

Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer

“…We observe that patients with a greater number of predicted chromothripsis events than average in their tumour genomes -or severe chromothripsis -had better prognoses than those patients with fewer or no chromothripsis events (Supp Table S12). Other cSV types, including ecDNA, showed weaker evidence for association with survival (Supp Table S12), contrary to previous pancancer reports 15 suggesting that the impact of ecDNA may differ in HGSOC from its impact in other tumour types.…”

“…HGSOC is subject to catastrophic mutational events, generating whole genome duplication (WGD) 9,10 , complex structural variants (cSV) such as chromothripsis or 'chromosome shattering' 11 , the production of extrachromosomal circular DNA (ecDNA) 12 and other cSV types involving overlapping amplifications and inversions 13,14 . However, the interdependencies between cSV types have not been studied in detail in any tumour type, including HGSOC, and their individual and joint impacts on patient survival remain poorly understood 15 . HGSOC tumour cells are also known to possess particularly abundant mitochondria carrying frequent somatic mtDNA mutations, though the best powered studies to date have failed to find associations between mitochondrial perturbation and patient outcomes [16][17][18] .…”

Pan-cancer analysis of chromothripsis-related gene expression patterns indicates an association with tumor immune and therapeutic agent responses

“…A great deal of evidence has shown that SVs associated with chromosome instability can have great impact on cells and are one of the main drivers of tumorigenesis ( 25 ). Chromothripsis is an extensive chromosomal rearrangement event, which typically has more complex effects than comparatively simple changes in a single chromosome segment, such as amplification, deletion or insertion.…”

Long-read sequencing of 945 Han individuals identifies novel structural variants associated with phenotypic diversity and disease susceptibility

“…Their findings also suggest that SV may account for an equal or even greater amount of genetic diversity in the human genome compared to single nucleotide polymorphisms (SNPs) which were previously thought to be the primary source of human phenotypic diversity and disease susceptibility differences 7,8 . While FISH, array-CGH, and ROMA have made significant contributions to SV detection, they have inherent limitations in resolution, breakpoint, and complex SV detection 4,5,[9][10][11] .…”