A pan-cancer compendium of chromosomal instability

Abstract

Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA 1 . The broad genomic complexity caused by CIN is a hallmark of cancer 2 ; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We present a compendium of 17 copy number signatures that characterize specific types of CIN, with putative aetiologies supported by multiple independent data sources. The signatures predict drug response and identify new drug targets. Our framework refines the understanding of impaired homologous recombination, which is one of the most therapeutically targetable types of CIN. Our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.CIN has complex consequences, including loss or amplification of driver genes, focal rearrangements, extrachromosomal DNA, micronuclei formation and activation of innate immune signalling 1 . This leads to associations with disease stage, metastasis, poor prognosis and therapeutic resistance 3 . The causes of CIN are also diverse and include mitotic errors, replication stress, homologous recombination deficiency (HRD), telomere crisis and breakage fusion bridge cycles, among others 1,4 .Because of the diversity of these causes and consequences, CIN is generally used as an umbrella term. Measures of CIN either divide tumours into broad categories of high or low CIN 5 , are restricted to a single aetiology such as HRD 6 , are limited to a particular genomic feature such as whole-chromosome-arm changes 7 , or can only be quantified in specific cancer types 8,9 . As a result, there is no systematic framework to comprehensively characterize the diversity, extent and origins of CIN pan-cancer, or to define how different types of CIN within a tumour relate to clinical phenotypes. Here we present a robust analysis framework to quantitatively measure different types of CIN across cancer types.

DETexT: An SNV detection enhancement for low read depth by integrating mutational signatures into TextCNN

“…Mutational processes from different etiologies are active during cancer development and can be identified by MS due to their unique mutational pattern and specific activity on the genome. The results reveal the diversity of mutational processes during the development of cancer and have potential implications for understanding cancer etiology (Tianyuan Liu et al, 2022 ), prevention (Aaron Chevalier et al, 2021 ), and therapy ( Drews et al, 2022 ).…”

“…There are 96 possible mutations as we incorporated six classes of base substitution: C > A, C > G, C > T, T > A, T > C, and T > G (referred to by the pyramiding of the mutated Watson-Crick base pair) as well as information on the 5′ and 3′ bases immediately adjacent to each mutated base, as shown in Figure 2D) (Alexandrov et al, 2013). The 96 substitution (Drews et al, 2022). The Catalogue Of Somatic Mutations In Cancer (COSMIC) database is the world's largest and most comprehensive resource for exploring the impact of somatic mutations on human cancer.…”

Chromatin structure in cancer

“…We anticipate further utility of spike-in normalized chromatin architectural sequencing in the context of chromosomal imbalances (e.g., aneuploidy), which occur in as much as 90% of human tumors [ 36 ]. Studies of childhood cancers which rarely exhibit signatures of high mutational frequencies but often display signs of chromothripsis [ 37 , 38 ] may benefit from these new approaches.…”

High-grade serous ovarian carcinoma organoids as models of chromosomal instability

“…Animal procedures were conducted in accordance with the local AWERB, NACWO and UK Home Office regulations (Animals Scientific Procedures Act 1986). 1.5x10 5…”