Disentangling the roles of aneuploidy, chromosomal instability and tumour heterogeneity in developing resistance to cancer therapies

Abstract

Aneuploidy is defined as the cellular state of having a number of chromosomes that deviates from a multiple of the normal haploid chromosome number of a given organism. Aneuploidy can be present in a static state: Down syndrome individuals stably maintain an extra copy of chromosome 21 in their cells. In cancer cells, however, aneuploidy is usually present in combination with chromosomal instability (CIN) which leads to a continual generation of new chromosomal alterations and the development of intratumour heterogeneity (ITH). The prevalence of cells with specific chromosomal alterations is further shaped by evolutionary selection, for example, during the administration of cancer therapies. Aneuploidy, CIN and ITH have each been individually associated with poor prognosis in cancer, and a wealth of evidence suggests they contribute, either alone or in combination, to cancer therapy resistance by providing a reservoir of potential resistant states, or the ability to rapidly evolve resistance. A full understanding of the contribution and interplay between aneuploidy, CIN and ITH is required to tackle therapy resistance in cancer patients. However, these characteristics often co-occur and are intrinsically linked, presenting a major challenge to defining their individual contributions. Moreover, their accurate measurement in both experimental and clinical settings is a technical hurdle. Here, we attempt to deconstruct the contribution of the individual and combined roles of aneuploidy, CIN and ITH to therapy resistance in cancer, and outline emerging approaches to measure and disentangle their roles as a step towards integrating these principles into cancer therapeutic strategy.

Patterns of Chromosomal Instability and Clonal Heterogeneity in Luminal B Breast Cancer

“…The findings of this study are in line with previous research, which suggests that ER+ tumors exhibit the lowest average CIN70 score [18]. CIN70 is a method used to determine the level of CIN from the expression of 70 specific genes consistently associated with aneuploidy in populations of tumor samples [20]. However, this method evaluates the level of CIN from a pool of cells, rather than assessing CIN cell by cell, as was done in this study using FISH with 6 centromeric probes.…”

Patterns of Chromosomal Instability and Clonal Heterogeneity in Luminal B Breast Cancer: A Pilot Study

“…The findings of this study are in line with previous research, which suggests that ER+ tumors exhibit the lowest average CIN70 score [18]. CIN70 is a method used to determine the level of CIN from the expression of 70 specific genes consistently associated with aneuploidy in populations of tumor samples [20]. However, this method evaluates the level of CIN from a pool of cells rather than assessing CIN cell by cell, as was done in this study using FISH with six centromeric probes.…”

YAP promotes chromosomal instability by transcriptionally activating AJUBA through its super enhancer in breast cancer

“…In our current research, we observed that YAP/TAZ could directly induce aberrant mitosis in breast cancer cells, thus cause abnormal chromosomal segregation and aneuploidy. In malignancy, aneuploidy often leads to a continual generation of new chromosomal alterations, thus causes chromosomal instability and the development of intratumor heterogeneity 1,39 . Several mechanisms underlying CIN have been proposed, including weakened spindle checkpoint signaling, supernumerary centrosomes, defects in chromatid cohesion, abnormal kinetochore-microtubule attachments and increased spindle microtubule dynamics 40 .…”