Novel driver gene MDC1 confers homologous recombination repair deficiency and genomic instability in chemoresistant relapsing ovarian cancer.
Nearly 80% of patients with High grade serous ovarian cancer (HGSOC) will experience recurrence within 5 years, but little is known about the mechanisms that drive this process. In this study we used whole genome sequencing to assess SNV and SV burdens. These were in turn used to estimate clonal dynamics, genomic scarring, and establish mutational patterns. Mutational burdens and clonal compositions are established early and are maintained throughout recurrence. Using both next generation and ultra long read sequencing to analyze single nucleotide and structural variants (SVs) we discovered that although tumors from the same patient remained relatively stable, homologous recombination repair proficient (HRP) and homologous recombination repair deficient (HRD) tumors presented with distinct clonal profiles. SV signature analysis revealed three distinct classes: tumors defined by DNA losses, DNA gains, and copy number neutral changes. Each class displayed structural variation affecting distinct regions of the genome. Ultra long read sequencing validated most of the SVs identified in short read sequencing and identified additional SVs. A novel candidate driver gene involved in DNA repair, MDC1, was significantly mutated in patients with HRP tumors. The phenotype of high grade serous ovarian tumors, as defined by mutation and clonality profiles, is established early in disease development and remain largely unchanged through chemotherapy and recurrence. This, when considered with the significant inter-patient heterogeneity identified in HGSOC, demonstrates the need for personalized therapies based on tumor profiling. Loss of MDC1 increases invasive properties in cell lines and may drive HRD in a subset of patients.
