Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome

John Thomson, Robb Hollis, Juliette van Baal, Narthana Ilenkovan, Michael Churchman, Koen van de Vijver, Alison M Meynert, Clare Bartos, Tzyvia Rye, Ian Croy, Patricia Diana, Mignon van Gent, Helen Creedon, Rachel Nirsimloo, Fiona Nussey, Christianne Lok, C Simon Herrington, Charlie Gourley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Low-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy.

Genomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation.

63 cases were analysed and three subgroups identified based on single nucleotide variants: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated gene mutation (MAPK-assoc: 27%) and MAPK wild-type (MAPKwt: 21%). NOTCH pathway disruption occurred across all subgroups. Tumour mutational burden (TMB), mutational signatures and recurrent copy number (CN) changes varied across the cohort with co-occurrence of chromosome 1p loss and 1q gain (CN Chr1pq) a recurrent feature. Low TMB and CN Chr1pq were associated with inferior disease-specific survival (HR 6.43; p < 0.001 and HR 3.29, p = 0.011 respectively). Stepwise genomic classification in relation to outcome resulted in four groups (TMB low; CN Chr1pq; MAPKwt/MAPKassoc; cMAPKm). 5 year disease-specific survival was 46%, 55%, 79% and 100% respectively for these groups. The two most favourable genomic subgroups were enriched for the SBS10b mutational signature, particularly the cMAPKm subgroup.

LGSOC comprises multiple genomic subgroups with distinct clinical and molecular features. Chr1pq CN arm disruption and TMB represent promising methods to identify individuals with poorer prognosis. Further investigation of the molecular basis for these observations is required. MAPKwt cases represent around a fifth of patients. NOTCH inhibitors represent a candidate therapeutic strategy worthy of exploration across these cases.
Original languageEnglish
JournalGynecologic Oncology
Publication statusPublished - 17 May 2023

Keywords / Materials (for Non-textual outputs)

  • low grade serous ovarian cancer
  • Genomics
  • Exome-sequencing
  • Molecular Profiling
  • MAPK


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