Development of an homologous recombination deficiency scoring algorithm for unmatched ovarian tumor sample based on next-generation sequencing.

Abstract

Objective: Poly (ADP-ribose) polymerase inhibitors (PARPis) have emerged as a novel targeted therapy, necessitating the development of PARPi sensitivity tests for clinical application. However, the requirement for matched normal tissue complicates clinical testing procedures and increases the burden on patients. In this study, we optimized a bioinformatics algorithm utilizing the Panel of Normals to accommodate tumor-only scenarios.

Methods: Paired samples from both clinical (Chinese population) and International Cancer Genome Consortium (ICGC) databases (Caucasian population) were employed to establish training cohorts. The tumor-only algorithm was developed based on these cohorts. The performance of the tumor-only algorithm was evaluated through linear regression against the paired sample algorithm. The validity of both algorithms was tested using progression-free survival data from patients treated with PARPis. Additionally, clinical samples from an independent institution were utilized to further validate the tumor-only algorithm.

Results: In the training sets, we observed high correlations between the tumor-only and paired sample algorithms regarding tumoral purity and homologous recombination deficiency (HRD) scores, with most R² values exceeding 0.9. In the validation set, a slight decrease in correlation was noted, although the majority of R² values remained close to 0.9. Both algorithms effectively distinguished PARPi-sensitive patients. No statistically significant differences were identified between the training and validation cohorts concerning clinical characteristics. Cross-racial validation yielded similar results.

Conclusion: The tumor-only algorithm demonstrated an equivalent capacity to the paired sample algorithm for classifying HRD status in ovarian cancer. This algorithm also showed cross-racial applicability, highlighting its potential for clinical use.