High-Grade Serous Ovarian Carcinoma in the Genomics Era: Current Applications, Challenges and Future Directions

High-grade serous ovarian carcinoma (HGSOC) is characterised by profound genomic instability and limited durable responses to standard therapy, leading to poor prognosis. The use of next-generation sequencing technologies has improved understanding of its molecular landscape, revealing consistent Tumour Protein p53 (TP53) mutations, homologous recombination defects, pathway alterations, and epigenetic dysregulation. Such genomic profiling now underpins the classification criteria between the ovarian cancer subtypes described by the Cancer Genome Atlas. Widespread chromosomal instability and pathogenic variants in multiple genes distinguish HGSOC from other subtypes of ovarian cancer and, further, from low-grade serous ovarian cancer. Importantly, the new-found understanding of the genomic landscape of HGSOC guides the use of platinum-based chemotherapies and Poly(ADP-ribose) Polymerase (PARP) inhibitors, with homologous recombination deficiency emerging as a cancer vulnerability that enhances treatment response. A combined multi-omics approach integrates transcriptomics, proteomics, metabolomics, and epigenomics to further the understanding of the characteristics, therapeutic targets and treatment resistance within HGSOC. Despite these advances, major challenges persist, including intratumoural heterogeneity and the poor diversity of genomic datasets. Artificial Intelligence (AI) technology, Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing, neoantigen-guided immunotherapy and ovarian cancer vaccination indicate a promising future for genomics-guided interventions and support the integration of genomics within multi-omic approaches to improve HGSOC outcomes.