Abstract 810: HRD is inversely correlated with MSI and identifies immunologically cold tumors in most cancer types
Authors: Budczies Jan , Kluck Klaus , Beck Susanne , Ouralidis Iordanis , Allgäuer Michael , Menzel Michael , Rempel Eugen , Kazdal Daniel , Perkhofer Lukas , Kleger Alexander , Schirmacher Peter , Seufferlein Thomas , Stenzinger Albrecht 
Published: June 2022

Abstract
Homologous recombination deficiency (HRD) leads to DNA double strand breaks and can be exploited by the use of PARP inhibitors to induce synthetic lethality of cancer cells. Over the last years, the clinical utility of this therapeutic concept was successfully demonstrated in ovarian, breast, prostate and pancreatic cancer. Currently, the role of HRD is investigated in trials testing immune checkpoint blockers alone or in combination with PARP inhibitors. But the relationship between HRD and immune cell contexture in cancer is incompletely understood. Here, we analyzed the association of HRD with tumor mutational burden (TMB), immune cell composition and gene expression in 10,000 tumors of 32 solid cancer types from the TCGA project. For each of the tumors, the HRD sum score (HRDsum) was calculated from allele-specific copy numbers (derived from genotyping data) and the TMB was calculated from the missense mutation calls (derived from WES data). HRDsum and tumor mutational burden (TMB) correlated positively pan-cancer (R=0.42) and within most cancer types. By contrast, HRD was absent in ultra-hypermutated (TMB &gt;= 100 mut/Mb) tumors. Ultra-hypermutation was typically associated with microsatellite instability (MSI) or POLE/POLD1 mutation. Significant positive correlation of the HRDsum and immune cell infiltration was observed pan-cancer, but only within a few cancer types. Significant positive correlation of HRDsum and the T-cell inflamed gene expression profile was observed only in 7 of 32 cancer types: in breast cancer, ovarian cancer, low grade glioma, testicular germ cell tumors and three kinds of kidney cancer. A functional genomics analysis was carried out by correlating genome-wide gene expression data (derived from RNA-Seq) with HRDsum. The resulting lists of significantly correlating genes were analyzed for enrichment of 50 hallmark gene sets (catalog H, MSigDB). We detected simultaneous enrichment of two proliferation-related categories, E2F_TARGETS and G2M_checkpoint, for 13 of the 32 cancer types (ACC, BLCA, BRCA, KIRC, KIRP, LGG, LIHC, LUAD, LUSC, MESO, PRAD, SARC, THYM). The study shows that HRD is associated with immunological activation of the tumor microenvironment only in a minority of cancer types. Our data support further studies of immune activating therapies in combination with immune checkpoint blockade in the not intrinsically activated cancer types and advocate to combine different genomic and transcriptomic biomarkers (including HRD and TMB) for comprehensive molecular diagnostics and therapy guidance.
Citation Format: Jan Budczies, Klaus Kluck, Susanne Beck, Iordanis Ouralidis, Michael Allgäuer, Michael Menzel, Eugen Rempel, Daniel Kazdal, Lukas Perkhofer, Alexander Kleger, Peter Schirmacher, Thomas Seufferlein, Albrecht Stenzinger. HRD is inversely correlated with MSI and identifies immunologically cold tumors in most cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 810.