Homologous Recombination Repair Mechanisms in Serous Endometrial Cancer

SIMPLE SUMMARY: Serous endometrial cancer is an unusual and aggressive endometrial cancer subtype, conferring the highest mortality of all endometrial cancers. In many ways, it resembles the more common tumor entity high-grade serous ovarian cancer. Thus, there is an urgent need for better treatment options for serous endometrial cancer patients. It is crucial for all dividing cells that the DNA repair is functioning correctly. Our aim was to investigate deficiencies in DNA repair in serous endometrial cancer, in particular the presence of homologous recombination repair deficiency. This kind of DNA repair defect may indicate that a specific targeted therapy, so-called PARP inhibitors, which are already in use for the treatment of ovarian cancer, may be useful also in serous endometrial cancer. This study contributes to the largely unexplored field of DNA repair deficiencies in serous endometrial cancer, and may hence contribute to future improved prognosis for these patients. ABSTRACT: Serous endometrial cancer (SEC) resembles high-grade serous ovarian cancer (HGSOC) genetically and clinically, with recurrent copy number alterations, TP53 mutations and a poor prognosis. Thus, SEC patients may benefit from targeted treatments used in HGSOC, e.g., PARP inhibitors. However, the preclinical and clinical knowledge about SEC is scarce, and the exact role of defective DNA repair in this tumor subgroup is largely unknown. We aimed to outline the prevalence of homologous recombination repair deficiency (HRD), copy-number alterations, and somatic mutations in SEC. OncoScan SNP arrays were applied to 19 tumors in a consecutive SEC series to calculate HRD scores and explore global copy-number profiles and genomic aberrations. Copy-number signatures were established and targeted sequencing of 27 HRD-associated genes was performed. All factors were examined in relation to HRD scores to investigate potential drivers of the HRD phenotype. Ten of the 19 SEC tumors (53%) had an HRD score > 42, considered to reflect an HRD phenotype. Higher HRD score was associated with loss of heterozygosity in key HRD genes, and copy-number signatures associated with non-BRCA1/2 dependent HRD in HGSOC. A high number of SECs display an HRD phenotype. It remains to be elucidated whether this also confers PARP inhibitor sensitivity.