The hidden genome of high-grade serous ovarian carcinoma: repetitive DNA, extrachromosomal DNA, and complex structural variation

High-grade serous ovarian carcinoma (HGSOC) is marked by extensive genomic instability, characterized by near-universal TP53 mutations, frequent homologous recombination deficiency (HRD), widespread copy-number alterations, and complex structural rearrangements. However, much of our current understanding of this molecular landscape has been derived from exome sequencing, microarrays, and short-read whole-genome sequencing, which are limited in their ability to resolve repetitive and structurally complex genomic regions. Long-read sequencing, together with telomere-to-telomere reference assemblies, is beginning to reveal previously inaccessible aspects of HGSOC genome architecture. Exploratory studies have reported centromeric and transposable-element hypomethylation, chromosome-arm-specific telomere shortening, and complex extrachromosomal DNA (ecDNA) architectures associated with enhancer regulation and transposable-element activity. Complementary studies have also identified ongoing LINE-1 retrotransposition in HGSOC. Together, these observations suggest that repetitive DNA, epigenetic instability, and complex genome architecture may contribute to HGSOC heterogeneity and tumor evolution, although their causal relationships remain uncertain. Nevertheless, genome-wide long-read evidence in HGSOC currently derives primarily from two small studies involving six and 12 patients, respectively, underscoring the need for validation in larger, independent cohorts.