Jan Budczies

CG>TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer

Abstract Homologous recombination deficiency (HRD) is a predictive biomarker for PARP inhibition and platinum-based chemotherapy. While copy number alteration-based scores such as HRDsum = LST + TAI + LOH are included in therapy approvals, single base substitutions (SBS) are underinvestigated as predictors of HRD. WES data of the TCGA pan-cancer cohort and an in-house ovarian cancer cohort were annotated by alterations in BRCA1/2 and additional genes causative of HRD. Using this reference, the new biomarker fdeam defined as frequency of C > T transitions at CpG sites in relation to all SBS and HRDsum were compared for the detection of HRD. In the TCGA ovarian cancer, the in-house, and the TCGA breast cancer cohorts, fdeam performed non-inferior to HRDsum (AUC = 0.84, AUC = 0.85, and AUC = 0.88). The cutpoint fdeam = 13.1% maximized the balanced accuracy in the TCGA ovarian cancer cohort and resulted in sensitivity = 89% and specificity = 77% in the in-house cohort. In a simulation study, fdeam retained high sensitivity for HRD detection and outperformed HRDsum in tumors of purity 40%, 20%, and 10%. Overcoming the limited robustness against low tumor purity, the new biomarker can contribute to a more sensitive detection of HRD in clinical samples. Further studies are warranted to confirm its clinical validity and utility and explore its potential for liquid biopsies.

Homologous recombination deficiency is inversely correlated with microsatellite instability and identifies immunologically cold tumors in most cancer types

AbstractHomologous recombination deficiency (HRD) leads to DNA double‐strand breaks and can be exploited by the use of poly (ADP‐ribose) polymerase (PARP) inhibitors to induce synthetic lethality. Extending the original therapeutic concept, the role of HRD is currently being investigated in clinical trials testing immune checkpoint blockers alone or in combination with PARP inhibitors, but the relationship between HRD and immune cell context in cancer is incompletely understood. We analyzed the association between immune cell composition, gene expression, and HRD in 9,041 tumors of 32 solid cancer types from The Cancer Genome Atlas (TCGA). The numbers of genomic scars were quantified by the HRD sum score (HRDsum) including loss of heterozygosity, large‐scale state transitions, and telomeric allelic imbalance. The T‐cell inflamed gene expression profile correlated weakly, but significantly positively, with HRDsum across cancer types (ρ = 0.17). Within individual cancer types, a significantly positive correlation was observed only in breast cancer, ovarian cancer, and four other cancer types, but not in the remaining 26 cancer types. HRDsum and tumor mutational burden (TMB) correlated significantly positively across cancer types (ρ = 0.42) and within 18 cancer types. HRDsum and a proliferation metagene correlated significantly positively across cancer types (ρ = 0.52) and within 20 cancer types. Mismatch repair deficiency and HRD as well as proofreading deficiency showed a high level of exclusivity. High HRD scores were associated with an immunologically activated tumor microenvironment only in a minority of cancer types. Our data favor the combination of genetic markers, complex genomic markers (including HRDsum and TMB), and other molecular markers (including proliferation scores) for a precise and comprehensive read‐out of the tumor biology and an individually tailored treatment.