# Examining the Concordance of Detection of Hereditary Cancer Gene Variants Between Blood, Tumour, and Normal Tissue in Patients with High-Grade Serous Ovarian Carcinoma

## TL;DR

This study shows that normal tissue from ovarian cancer surgeries can reliably detect inherited cancer gene variants, similar to blood tests.

## Contribution

The study demonstrates that archived normal tissue can be used as a reliable alternative to blood for germline variant detection in ovarian cancer patients.

## Key findings

- Normal tissue testing detected all germline variants confirmed by blood testing in 23 out of 24 cases.
- No false positives or negatives were found when comparing normal tissue and blood test results.
- The approach could improve triage for genetic counseling in high-grade serous ovarian carcinoma patients.

## Abstract

Background/Objectives: Access to genetic counselling and BRCA1/2 germline testing is standard of care for patients with high-grade serous ovarian carcinoma (HGSOC). While tumour testing reliably detects pathogenic variants in hereditary cancer genes, it cannot distinguish somatic from germline variants. Concurrent testing of non-cancerous (normal) tissue obtained during surgery may improve triage for germline testing and clinical genetics referral. This study evaluated the concordance of inherited variant detection among tumour, normal tissue, and blood to determine whether archived normal tissue can reliably identify germline pathogenic variants. Methods: Patients with HGSOC who had a pathogenic variant identified by targeted Next Generation Sequencing (NGS) tumour testing and underwent germline hereditary cancer gene panel (HCP) testing between April 2019 and November 2020 were included. HCP testing was performed on formalin-fixed, paraffin-embedded normal tissue from the original resection. Variant results were compared across tumour, normal tissue, and germline (blood) samples to determine concordance, false-negative, and false-positive rates. Results: Forty-one patients had confirmed tumour variants in BRCA1/2 or other HCP genes. Of these, 24 harboured a corresponding germline pathogenic variant. Archived normal tissue was available for 23 of these 24 cases, and all germline variants were detected in normal tissue, showing 100% concordance. Among the 17 patients without germline variants, all corresponding normal tissue samples were negative, also demonstrating 100% concordance. No false positives or negatives were identified. Conclusions: NGS testing of normal tissue at surgical resection reliably identifies germline pathogenic variants in patients with HGSOC. Incorporating this approach may help triage patients for clinical genetics assessment.