Characterizing chromosome instability in chemonaïve, chemosensitive and chemoresistant high-grade serous ovarian cancer

Abstract

High-grade serous ovarian cancer (HGSOC) is the most common and lethal gynaecological malignancy in women. The high level of mortality in HGSOC patients is attributed to late stage diagnoses, highly aggressive metastatic disease, disease recurrence and drug resistance. Currently, little is known about the underlying mechanisms driving tumor recurrence and drug resistance in HGSOC. Chromosome instability (CIN; an increased rate of chromosome gains and losses) is one mechanism associated with multi-drug resistance and tumor recurrence in many cancer types, but has only just begun to be characterized in HGSOC. I hypothesize that CIN is prevalent in HGSOC, is associated with HGSOC progression and will increase in recurrent and chemoresistant disease. Using a combination of quantitative imaging microscopy and cytogenetic approaches, I investigate the prevalence and unique temporal dynamics of CIN in ascites derived patient samples and solid tumor samples collected from HGSOC patients, encompassing chemonaïve, chemosensitive and chemoresistant disease. CIN was prevalent in 92.5% of HGSOC ascites derived patient samples and 100% of HGSOC solid tumors. Further in-depth analyses demonstrated that serial ascites derived HGSOC patient samples exhibit statistically significant changes over time (i.e. temporal dynamics). Importantly, aneuploidy and CIN increases with disease progression and recurrence, and CIN exhibits varied dynamics during and following chemotherapy, highlighting CIN as a potential biomarker of disease progression.