Chromosome instability is prevalent and dynamic in high-grade serous ovarian cancer patient samples

Abstract

Objective: High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological malignancy in women with a high level of mortality, metastatic disease, disease recurrence and multi-drug resistance. Many previous studies have focused on characterising genome instability in recurrent resistant HGSOC and while this has advanced our understanding of HGSOC, our fundamental knowledge of the mechanisms driving genome instability remains limited. Chromosome instability (CIN; an increased rate of chromosome gains and losses) is a form of genome instability that is commonly associated with recurrence and multi-drug resistance in many cancer types but has just begun to be characterised in HGSOC.

Method: To examine the relationship between CIN and HGSOC, we employed single-cell quantitative imaging microscopy approaches capable of capturing the cell-to-cell heterogeneity associated with CIN, to assess the prevalence and dynamics of CIN within individual and patient-matched HGSOC ascites and solid tumour samples.

Results: CIN occurs in 90.9% of ascites samples and 100% of solid tumours, while in-depth analyses identified statistically significant temporal dynamics within the serial ascites samples. In general, aneuploidy and CIN increase with disease progression and frequently decrease following chemotherapy treatments in responsive disease. Finally, our work identified higher levels of CIN in solid tumours relative to ascites samples isolated from the same individual, which identifies a novel difference existing between solid tumours and ascites samples.

Conclusions: Our findings provide novel insight into the relationship between CIN and HGSOC, and uncover a previously unknown relationship existing between CIN in solid tumours and metastatic disease (ascites).

Keywords: CIN score; Chromosome enumeration probe; Chromosome instability; High-grade serous ovarian cancer; Intratumoural heterogeneity; Ovarian cancer; Patient samples; Quantitative imaging microscopy; Recurrence; Resistance.