Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study

Dhivya Chandrasekaran, Monika Sobocan, Oleg Blyuss, Rowan E. Miller, Olivia Evans, Shanthini M. Crusz, Tina Mills-Baldock, Li Sun, Rory F. L. Hammond, Faiza Gaba, Lucy A. Jenkins, Munaza Ahmed, Ajith Kumar, Arjun Jeyarajah, Alexandra C. Lawrence, Elly Brockbank, Saurabh Phadnis, Mary Quigley, Fatima El Khouly, Rekha WuntakalAsma Faruqi, Giorgia Trevisan, Laura Casey, George J. Burghel, Helene Schlecht, Michael Bulman, Philip Smith, Naomi L. Bowers, Rosa Legood, Michelle Lockley, Andrew Wallace, Naveena Singh, D. Gareth Evans, Ranjit Manchanda

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We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p 0.001). The median age was 54 (IQR = 51–62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51–71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes.
Original languageEnglish
Article numbere4344
Issue number17
Early online date27 Aug 2021
Publication statusE-pub ahead of print - 27 Aug 2021


  • ovarian cancer
  • BRCA
  • genetic testing
  • germline
  • somatic
  • RAD51C
  • RAD51D
  • BRIP1


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