Abstract 3538: Microsatellite instability (MSI) and homologous recombination deficiency (HRD) are mutually exclusive mechanisms of genomic instability

Background: Genomic instability refers to the tendency to accumulate genomic alterations. MSI-High (MSI-H) tumors are characterized by a mismatch repair deficiency triggering hypermutation, whereas HRD tumors display genomic lesions that result in genomic loss of heterozygosity (gLOH). These mechanistic differences have critical implications for treatment strategies, where immune checkpoint blockade is often efficacious in MSI-H tumors and PARP inhibition is linked to response in HRD tumors. We investigated the patterns of co-occurrence or mutual exclusivity between these two mechanisms of genomic instability. Methods: Comprehensive genomic profiling was performed on >130K tumors to coding exons and select introns of up to 465 genes. MSI was determined on up to 114 loci and high gLOH (≥14%) was used as a surrogate of HRD (PMID: 27908594). Results: In this cohort, HRD was most prevalent in triple-negative breast and fallopian tube cancers and absent in cancers such as skin neuroendocrine cancers. HRD was strongly associated with biallelic loss of homologous recombination (HR) pathway genes and not monoallelic loss of these genes. High MSI was most frequently found in endometrial and small intestine cancers, and absent in cancers such as fallopian tube cancers and GIST. MSI-H tumors and HRD tumors were mutually exclusive (6.5% of MSI-H tumors were HRD vs 25.7% of tumors that were not MSI-H; OR = 5.0; p Conclusions: We show that high MSI and HRD events are mutually exclusive across tumor types, suggesting that co-occurrence of these genomic instability mechanisms may be evolutionarily disadvantageous. High gLOH is associated with biallelic loss of HR pathway genes, supporting its use as a surrogate for HRD. The genomic differences between HRD and MSI-H may underlie differential susceptibility to targeted therapeutics. Citation Format: Dexter X. Jin, Ethan S. Sokol, Sally E. Trabucco, Garrett M. Frampton, Luciana Molinero. Microsatellite instability (MSI) and homologous recombination deficiency (HRD) are mutually exclusive mechanisms of genomic instability [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3538.