Determinants and clinical implications of chromosomal instability in cancer

Abstract

Aberrant chromosomal architecture, ranging from small insertions or deletions to large chromosomal alterations, is one of the most common characteristics of cancer genomes. Chromosomal instability (CIN) underpins much of the intratumoural heterogeneity observed in cancers and drives phenotypic adaptation during tumour evolution. Thus, an urgent need exists to increase our efforts to target CIN as if it were a molecular entity. Indeed, CIN accelerates the development of anticancer drug resistance, often leading to treatment failure and disease recurrence, which limit the effectiveness of most current therapies. Identifying novel strategies to modulate CIN and to exploit the fitness cost associated with aneuploidy in cancer is, therefore, of paramount importance for the successful treatment of cancer. Modern sequencing and analytical methods greatly facilitate the identification and cataloguing of somatic copy-number alterations and offer new possibilities to better exploit the dynamic process of CIN. In this Review, we describe the principles governing CIN propagation in cancer and how CIN might influence sensitivity to immune-checkpoint inhibition, and survey the vulnerabilities associated with CIN that offer potential therapeutic opportunities.

Quantifying local malignant adaptation in tissue-specific evolutionary trajectories by harnessing cancer’s repeatability at the genetic level

“…Fig. 4), in agreement with the role of TP53 in promoting genome instability, which then accelerates CNA acquisition (Martinez et al, 2016;Sansregret, Vanhaesebroeck, & Swanton, 2018).…”

GRIDSS, PURPLE, LINX: Unscrambling the tumor genome via integrated analysis of structural variation and copy number

“…Copy number alteration (CNA) and structural variation (SV) are two of the key classes of somatic mutations in cancer with approximately 90% of tumors undergoing significant rearrangement [1]. Despite the critical and interrelated role of SV and CNA in tumorigenesis [2], the mechanisms driving and consequences of genomic rearrangements in cancer are less well understood than for point mutation events, and less frequently used as biomarkers for clinical purposes. This is due both to the relative paucity of whole genome sequencing data which is required for SV analysis, but also the fact that genomic rearrangements have significant diversity and in many cases a high degree of complexity with individual events involving multiple or even up to hundreds of breaks [3,4].…”

p53 induces senescence in the unstable progeny of aneuploid cells

“…Despite impairing the proliferative capacity of individual cells, aneuploidy correlates with cancer evolution and therapy resistance [2], possibly due to the fitness advantages this confers under specific environmental and genetic conditions [3][4][5][6][7]. Moreover, since aneuploidy has been shown to cause genetic and chromosomal instability (CIN) in both yeast and mammalian cells [8][9][10][11], this state may promote the generation of heterogeneous populations that support cancer development and tumor acquisition of drug resistant traits [7,12,13]. Given this risk of potential pathological changes, multicellular organisms have evolved a range of different strategies to curb the proliferation of aneuploid cells.…”