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

## TL;DR

This study introduces a new biomarker for detecting homologous recombination deficiency in ovarian and breast cancer using single base substitutions, which works well even in low tumor purity samples.

## Contribution

A new biomarker using single base substitutions is proposed as a non-inferior alternative to copy number-based HRD detection.

## Key findings

- The new biomarker fdeam performed non-inferior to HRDsum in multiple cancer cohorts.
- fdeam retained high sensitivity for HRD detection in simulated low tumor purity samples.
- The cutpoint fdeam = 13.1% achieved high sensitivity and specificity in ovarian cancer samples.

## 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.

Using single base substitutions instead of copy number alterations is a non-inferior approach for the detection of homologous recombination deficiency in ovarian and breast cancer overcoming limits for samples of low tumor purity.