Intratumoural heterogeneity and the evolution of drug resistance in high-grade serous ovarian cancer


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James Brenton1
1Cancer Research UK Cambridge Research Institute, Cambridge, UK

Abstract

Background

High-grade serous ovarian carcinoma (HGSOC) is clinically defined by ubiquitous loss ofTP53 and profound genomic instability, which may allow the parallel evolution of diverse subpopulations. Intratumoral genetic heterogeneity was first described by Dexter in 1978 and has been linked to the emergence of drug resistance in leukaemias. We have recently shown that cell lines derived after clinically-acquired platinum resistance represent a distinct subpopulation that are not linearly related to cell lines established prior to treatment. We have also shown that different genetic subpopulations exist at diagnosis in locally advanced cervical cancer and subpopulations show different responses and repopulation during chemoradiotherapy. These data imply that multiple subclonal genetic populations may exist in patients with HGSOC and that drug resistance could result from selection of these clones by chemotherapy.

Methods
To demonstrate the presence of heterogeneity and to delineate the tumour evolutionary history, we carried out 180 Affymetrix SNP6 array comparative genomic hybridisations to profile multiple biopsies (range 1-29) from 20 cases of stage III/IV HGSOC taken from different metastatic sites and before and after neoadjuvant platinum-based chemotherapy.

Results
Four patients had divergent array CGH profiles at≥2 metastatic sites.We have reconstructed the phylogeny of these cases using finite state transducers to quantify the extent of divergence from the putative common ancestor. These studies have identified driver events and provide evidence for clonal selection of specific aberrations in later relapse disease. Detailed studies using paired-end DNA sequencing for structural variation and candidate gene resequencing are ongoing.

Conclusions
Intratumoural heterogeneity can be identified in a spatial distribution in cases from high-grade serous ovarian cancer. Detailed biological studies of subclonal populations will be required to test if they contain drug resistant cells.