Real-World Concordance between Germline and Tumour BRCA1/2 Status in Epithelial Ovarian Cancer

Robert D Morgan; George J Burghel; Helene Schlecht; Andrew R Clamp; Jurjees Hasan; Claire L Mitchell; Zena Salih; Joseph Shaw; Sudha Desai; Gordon C Jayson; Emma R Woodward; D Gareth R Evans

doi:10.3390/cancers16010177

Real-World Concordance between Germline and Tumour BRCA1/2 Status in Epithelial Ovarian Cancer

Cancers (Basel). 2023 Dec 29;16(1):177. doi: 10.3390/cancers16010177.

Authors

Robert D Morgan^{1

2}, George J Burghel^{3

4}, Helene Schlecht³, Andrew R Clamp^{1

2}, Jurjees Hasan¹, Claire L Mitchell¹, Zena Salih¹, Joseph Shaw⁵, Sudha Desai⁶, Gordon C Jayson^{1

2}, Emma R Woodward^{3

4

7}, D Gareth R Evans^{3

4

7}

Affiliations

¹ Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK.
² Division of Cancer Sciences, Faculty of Biology, Medicine and Health, School of Medical Sciences, University of Manchester, Manchester M13 9PL, UK.
³ North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust, Oxford Road, Manchester M13 9WL, UK.
⁴ Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, Manchester M13 9PL, UK.
⁵ Department of Gynaecological Pathology, Manchester University NHS Foundation Trust, Oxford Road, Manchester M13 9WL, UK.
⁶ Department of Pathology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK.
⁷ Department of Clinical Genetics, Manchester University NHS Foundation Trust, Oxford Road, Manchester M13 9WL, UK.

Abstract

Patients diagnosed with epithelial ovarian cancer may undergo reflex tumour BRCA1/2 testing followed by germline BRCA1/2 testing in patients with a positive tumour test result. This testing model relies on tumour BRCA1/2 tests being able to detect all types of pathogenic variant. We analysed germline and tumour BRCA1/2 test results from patients treated for epithelial ovarian cancer at our specialist oncological referral centre. Tumour BRCA1/2 testing was performed using the next-generation sequencing (NGS)-based myChoice^® companion diagnostic (CDx; Myriad Genetics, Inc.). Germline BRCA1/2 testing was performed in the North West Genomic Laboratory Hub using NGS and multiplex ligation-dependent probe amplification. Between 11 April 2021 and 11 October 2023, 382 patients were successfully tested for tumour BRCA1 and BRCA2 variants. Of these, 367 (96.1%) patients were tested for germline BRCA1/2 variants. In those patients who underwent tumour and germline testing, 15.3% (56/367) had a BRCA1/2 pathogenic variant (36 germline and 20 somatic). All germline BRCA1/2 pathogenic small sequencing variants were detected in tumour DNA. By contrast, 3 out of 8 germline BRCA1/2 pathogenic large rearrangements were not reported in tumour DNA. The overall concordance of germline BRCA1/2 pathogenic variants detected in germline and tumour DNA was clinically acceptable at 91.7% (33/36). The myChoice^® CDx was able to detect most germline BRCA1/2 pathogenic variants in tumour DNA, although a proportion of pathogenic large rearrangements were not reported. If Myriad's myChoice^® CDx is used for tumour BRCA1/2 testing, our data supports a testing strategy of germline and tumour BRCA1/2 testing in all patients diagnosed with epithelial ovarian cancer aged < 79 years old, with germline BRCA1/2 testing only necessary for patients aged ≥ 80 years old with a tumour BRCA1/2 pathogenic variant.

Keywords: BRCA1; BRCA2; germline; ovarian cancer; somatic.

Grants and funding

This research study received no external funding. E.R.W. and D.G.R.E. are supported by the Manchester National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (IS-BRC-1215–20007).