Clonal evolution of high‐grade serous ovarian carcinoma from primary to recurrent disease

Abstract

High-grade serous carcinoma (HGSC) is the most common and fatal form of ovarian cancer. While most tumours are highly sensitive to cytoreductive surgery and platinum- and taxane-based chemotherapy, the majority of patients experience recurrence of treatment-resistant tumours. The clonal origin and mutational adaptations associated with recurrent disease are poorly understood. We performed whole exome sequencing on tumour cells harvested from ascites at three time points (primary, first recurrence, and second recurrence) for three HGSC patients receiving standard treatment. Somatic point mutations and small insertions and deletions were identified by comparison to constitutional DNA. The clonal structure and evolution of tumours were inferred from patterns of mutant allele frequencies. TP53 mutations were predominant in all patients at all time points, consistent with the known founder role of this gene. Tumours from all three patients also harboured mutations associated with cell cycle checkpoint function and Golgi vesicle trafficking. There was convergence of germline and somatic variants within the DNA repair, ECM, cell cycle control, and Golgi vesicle pathways. The vast majority of somatic variants found in recurrent tumours were present in primary tumours. Our findings highlight both known and novel pathways that are commonly mutated in HGSC. Moreover, they provide the first evidence at single nucleotide resolution that recurrent HGSC arises from multiple clones present in the primary tumour with negligible accumulation of new mutations during standard treatment.

Role of chromosomal instability in cancer progression

“…Chromosomal instability predicts drug resistance and poor prognosis in multiple cancer types , McGranahan et al 2012 with several recent studies demonstrating the impact of chromosomal instability, tumour heterogeneity and clonal evolution on chemotherapy resistance and metastasis (Bakhoum et al 2011, Gerlinger et al 2012, McGranahan et al 2012, Bashashati et al 2013, Castellarin et al 2013, Murugaesu et al 2015, Jamal-Hanjani et al 2017. Chromosomal instability thus renders tumours more difficult to treat, but precise reasons for this are currently poorly defined.…”

Surveillance of the Tumor Mutanome by T Cells during Progression from Primary to Recurrent Ovarian Cancer

“…Patients had a diagnosis of HGSC and underwent standard treatment consisting of surgery followed by carboplatin-based chemotherapy with or without paclitaxel. Further clinical details can be found in our previous publication (31).…”

“…We recently performed whole exome sequencing of matched primary and recurrent tumor samples from 3 patients with HGSC (31). By comparing samples collected at primary surgery, first recurrence, and second recurrence, we showed that the HGSC mutanome evolves over time, likely reflecting the growth dynamics of different tumor cell subpopulations, as well as the acquisition of new mutations during chemotherapy.…”

Tumor-Infiltrating Plasma Cells Are Associated with Tertiary Lymphoid Structures, Cytolytic T-Cell Responses, and Superior Prognosis in Ovarian Cancer

“…As a result, HGSC exhibits a high degree of spatial heterogeneity involving potentially dozens of genomically distinct subclones with extensive dissemination across metastatic sites (5-7). Although HGSC is highly sensitive to primary platinum-based chemotherapy, the development of chemoresistant disease is common and can bring profound changes in subclonal architecture and mutation profiles (6)(7)(8).…”