Frequent homologous recombination deficiency in high-grade endometrial carcinomas.

Purpose The elevated levels of somatic copy number alterations (SCNA) in a subset of high-risk endometrial cancers (EC) are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in EC and its association with histopathological and molecular characteristics. Experimental Design Fresh tumor tissue was prospectively collected from 36 EC, and functional HRD was examined by the ability of replicating tumor cells to accumulate RAD51 protein at DNA double strand breaks (RAD51 foci) induced by ionizing radiation. Genomic alterations were determined by next generation sequencing and array comparative genomic hybridization/SNP array. The prevalence of BRCA-associated genomic scars-a surrogate marker for HRD-was determined in the TCGA EC cohort. Results Most EC included in the final analysis (n=25) were of non-endometrioid (52%), grade 3 (60%) histology and FIGO-stage I (72%). HRD was observed in 24% (n=6) of cases and was restricted to non-endometrioid EC (NEEC), with 46% of NEEC being HRD compared to none of the endometrioid EC (EEC, P=0.014). All but one of the HRD cases harboured either a pathogenic BRCA1 variant or high somatic copy number losses of HR genes. Analysis of TCGA cases supported these results, with BRCA-associated genomic scars present in up to 48% (63/132) of NEEC vs. 12% (37/312) of EEC (P<0.001). Conclusions HRD occurs in EC, and is largely restricted to non-endometrioid, TP53-mutant EC. Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors.

https://ift.tt/2T0bsML