Genetic heterogeneity and evolutionary history of high-grade ovarian carcinoma and matched distant metastases

Abstract

Background: High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian carcinoma, associated with poor clinical outcome and metastatic disease. Although metastatic processes are becoming more understandable, the genomic landscape and metastatic progression in HGSOC has not been elucidated.

Methods: Multi-region whole-exome sequencing was performed on HGSOC primary tumours and their metastases (n = 33 tumour regions) from six patients. The resulting somatic variants were analysed to delineate tumour evolution and metastatic dissemination, and to compare the repertoire of events between primary HGSOC and metastasis.

Results: All cases presented branching evolution patterns in primary HGSOC, with three cases further showing parallel evolution in which different mutations on separate branches of a phylogenetic tree converge on the same gene. Furthermore, linear metastatic progression was observed in 67% of cases with late dissemination, in which the metastatic tumour mostly acquires the same mutational process active in primary tumour, and parallel metastatic progression, with early dissemination in the remaining 33.3% of cases. Metastatic-specific SNVs were further confirmed as late dissemination events. We also found the involvement of metastatic-specific driver events in the Wnt/β-catenin pathway, and identified potential clinically actionable events in individual patients of the metastatic HGSOC cohort.

Conclusions: This study provides deeper insights into clonal evolution and mutational processes that can pave the way to new therapeutic targets.

Fig. 1. Distribution of alterations through HGSOC metastatic tumour progression.

a Overall percentage of CNVs (n = 852) and mutations (n = 1195) shared between the primary and metastasis, specific to the primary and specific to the metastasis. b Venn diagrams show the number of unique and shared mutations in primary and metastatic tumours in each case; ‘P’ represents primary tumour, ‘CO’ represents the contralateral ovarian metastatic tumour and ‘M’ represents metastatic tumour. Venn diagrams are not to scale. c All cancer driver mutations (SNVs and Indels) detected for each HGSOC primary and corresponding metastasis, including contralateral ovary metastasis, where relevant. The top panel displays the number of driver mutations/patient identified across tumours, whereas the right panel shows the total count of driver mutations/gene.

Fig. 2. Evolution of HGSOC metastasis.

Evolution of HGSOC metastasis based on cell fractions at different time points, depicting the history of individual clusters over time. Different colours represent separate clusters in a sample. Centred in relevant clusters are driver genes (in red), and parallel events converging at cancer genes (in blue) and non-cancer genes (in black).

Fig. 3. Phylogenetic tree summary.

Phylogenetic trees for six HGSOC tumours from primary to metastasis. Highlighted are driver genes (in red), and parallel events converging at cancer genes (in blue) and non-cancer genes (in black). Different coloured nodes represent distinct clones. Arrows indicate unidirectional metastatic progression after X% shared mutations at primary tumour to stated regional and distant sites. Clones specific to primary tumour tissues, ablated by therapy, not selected during metastatic seeding or occurred after metastatic seeding, have been outlined with red dashed lines. New clones in metastatic tumour tissues have been outlined with dark green dashed lines.

Fig. 4. Mutational signature processes in HGSOC metastasis.

a The percentage mutational contribution, in primary HGSOC and metastasis, to the 30 published mutational signatures from the COSMIC database. Increasing intensity represents increasing contribution of mutations. b The overall mutational contribution from the cohort to the 30 mutational signatures at primary and metastasis. Integers for significantly correlated signatures have been presented. ‘P’ represents primary tumour, ‘CO’ contralateral ovarian metastatic tumour and ‘M’ metastatic tumour.

Fig. 5. Final molecular time of metastatic diversions and clinically actionable events in HGSOC metastasis.

a Metastatic tumours disseminate after a median of ~78% molecular time. Primary tumours show more genomic similarities with distant metastases compared with contralateral ovarian tumours. Driver mutations were mostly shared by primary, distant metastasis and contralateral tumours. Potentially clinically actionable events in the metastatic HGSOC cohort have been indicated, where (b) a more detailed overview of actionable events in individual cases is also presented. All clinically actionable genes were detected for each primary HGSOC, contralateral ovary metastasis (where relevant) and the corresponding distant metastasis. The top panel shows the number of actionable genes per case identified across the tumour types in a case, whereas the right-hand side panel shows the percentage of actionable variants per gene found across the cohort. On the left-hand side panel, genes coloured red are driver cancer genes, blue are non-driver cancer genes and in black are the non-cancer genes. ‘Amp’ represents gene amplifications, ‘Del’ represents gene deletions, ‘P’ represents primary HGSOC tumour, ‘CO’ represents contralateral ovary metastasis, where relevant and ‘M’ represents metastatic tumour lesions.