Mechanisms of Chromosomal Instability in High-grade Serous Ovarian Carcinoma

Abstract

Chromosomal instability (CIN), the continual gain and loss of chromosomes or parts of chromosomes, occurs in the majority of cancers and confers poor prognosis. Mechanisms driving CIN remain unknown in most cancer types due to a scarcity of functional studies.High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynaecological malignancy in the Western world with chemotherapy resistance developing in almost all patients. HGSC exhibits high rates of chromosome aberrations and knowledge of causative mechanisms is likely to represent an important step towards combating the poor prognosis of this disease. However, very little is known about the nature of chromosomal instability exhibited by this cancer type in particular due to a historical lack of appropriate cell line models. Here we perform the first in-depth functional characterisation of mechanisms driving CIN in HGSC by analysing eight cell lines that accurately recapitulate HGSC genetics as defined by recent studies. We show, using a range of established functional CIN assays combined with live cell imaging and single molecule DNA fibre analysis, that multiple mechanisms co-exist to drive CIN in HGSC.These include supernumerary centrosomes, elevated microtubule dynamics and DNA replication stress. By contrast, the spindle assembly checkpoint was intact. These findings are relevant for developing therapeutic approaches to manipulating CIN in ovarian cancer, and suggests that such approaches may need to be multimodal to combat multiple co-existing CIN drivers.

DNA Replication Stress Generates Distinctive Landscapes of DNA Copy Number Alterations and Chromosome Scale Losses

“…Most cancers exhibit chromosomal instability (CIN) that generates somatic copy number alterations, fuels tumour genome evolution, and is associated with poor prognosis. Replication stress drives chromosomal instability (CIN) in multiple cancer types 1,2 and induced pluripotent stem cells 3 and can be driven by oncogenes 4,5 , low nucleoside concentrations 6,7 and difficult to replicate DNA sequences or structures 8,9 . High levels of replication stress can activate cell cycle checkpoints and lead to senescence that can form a barrier to tumour initiation 10,11 .…”