High-grade serous ovarian carcinoma organoids as models of chromosomal instability

Abstract

High-grade serous ovarian carcinoma (HGSOC) is the most genomically complex cancer, characterised by ubiquitous TP53 mutation, profound chromosomal instability and heterogeneity. The mutational processes driving chromosomal instability in HGSOC can be distinguished by specific copy number signatures. To develop clinically relevant models of these mutational processes we derived 15 continuous HGSOC patient-derived organoids (PDOs). We carried out detailed bulk transcriptomic, bulk genomic, single cell genomic, and drug sensitivity characterisation of the organoids. We show that PDOs comprise communities of different clonal populations and represent models of different causes of chromosomal instability including homologous recombination deficiency, chromothripsis, tandem-duplicator phenotype and whole genome duplication. We also show that these PDOs can be used as exploratory tools to study transcriptional effects of copy number alterations as well as compound-sensitivity tests. In summary, HGSOC PDO cultures provide a genomic tool for studies of specific mutational processes and precision therapeutics.

Predicting response to cytotoxic chemotherapy

“…These samples were subjected to low-pass whole-genome sequencing and in vitro treatment with doxorubicin (see Methods and Figure 1b for sample workflow). Further characterisation of these collections of patient derived spheroids and patient derived organoids can be found in parallel studies 10,12 .…”

“…In this way, CIN signatures give us the opportunity to identify potential biological mechanisms to target therapeutically. Initially prototyped in ovarian cancer 9 and then extended pan-cancer 8 , these signatures have shown potential to predict response to platinum-based chemotherapy in patients across multiple cancers 8 and other cytotoxic chemotherapies in a preclinical setting 8,10 . The full spectrum of signatures can be quantified in a tumour using standard genomic gene panels tests or shallow whole genome sequencing.…”