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

Dhivya Chandrasekaran^{1

2}, Monika Sobocan^{1

2

3}, Oleg Blyuss^{4

5

6}, Rowan E Miller⁷, Olivia Evans¹, Shanthini M Crusz⁷, Tina Mills-Baldock⁸, Li Sun^{1

9}, Rory F L Hammond¹⁰, Faiza Gaba¹, Lucy A Jenkins¹¹, Munaza Ahmed¹¹, Ajith Kumar¹¹, Arjun Jeyarajah², Alexandra C Lawrence², Elly Brockbank², Saurabh Phadnis², Mary Quigley⁸, Fatima El Khouly⁸, Rekha Wuntakal¹², Asma Faruqi¹⁰, Giorgia Trevisan¹⁰, Laura Casey¹⁰, George J Burghel¹³, Helene Schlecht¹³, Michael Bulman¹³, Philip Smith¹³, Naomi L Bowers¹³, Rosa Legood⁹, Michelle Lockley¹⁴, Andrew Wallace¹³, Naveena Singh¹⁰, D Gareth Evans¹³, Ranjit Manchanda^{1

2

9}

Affiliations

¹ Wolfson Institute of Population Health, Barts CRUK Cancer Centre, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
² Department of Gynaecological Oncology, Barts Health NHS Trust, London EC1 1BB, UK.
³ Divison for Gynaecology and Perinatology, University Medical Centre Maribor, 2000 Maribor, Slovenia.
⁴ School of Physics, Engineering and Computer Science, University of Hertfordshire, Hatfield AL10 9AB, UK.
⁵ Department of Paediatrics and Paediatric Infectious Diseases, Sechenov First Moscow State Medical University, Moscow 119991, Russia.
⁶ World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow 119991, Russia.
⁷ Department of Medical Oncology, Barts Health NHS Trust, London EC1A 7BE, UK.
⁸ Department of Medical Oncology, Barking, Havering & Redbridge University Hospitals, Essex RM7 0AG, UK.
⁹ Department of Health Services Research, Faculty of Public Health & Policy, London School of Hygiene & Tropical Medicine, London WC1H 9SH, UK.
¹⁰ Department of Pathology, Barts Health NHS Trust, London E1 1FR, UK.
¹¹ North East Thames Regional Genetics Service, Great Ormond Street Hospital, London WC1N 3JH, UK.
¹² Department of Gynaecology, Barking, Havering & Redbridge University Hospitals, Essex RM7 0AG, UK.
¹³ Manchester Centre for Genomic Medicine, Saint Marys Hospital, Manchester M13 9WL, UK.
¹⁴ Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

PMID: 34503154
PMCID: PMC8431198
DOI: 10.3390/cancers13174344

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

Dhivya Chandrasekaran et al. Cancers (Basel). 2021.

. 2021 Aug 27;13(17):4344.

doi: 10.3390/cancers13174344.

Authors

Affiliations

¹ Wolfson Institute of Population Health, Barts CRUK Cancer Centre, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
² Department of Gynaecological Oncology, Barts Health NHS Trust, London EC1 1BB, UK.
³ Divison for Gynaecology and Perinatology, University Medical Centre Maribor, 2000 Maribor, Slovenia.
⁴ School of Physics, Engineering and Computer Science, University of Hertfordshire, Hatfield AL10 9AB, UK.
⁵ Department of Paediatrics and Paediatric Infectious Diseases, Sechenov First Moscow State Medical University, Moscow 119991, Russia.
⁶ World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow 119991, Russia.
⁷ Department of Medical Oncology, Barts Health NHS Trust, London EC1A 7BE, UK.
⁸ Department of Medical Oncology, Barking, Havering & Redbridge University Hospitals, Essex RM7 0AG, UK.
⁹ Department of Health Services Research, Faculty of Public Health & Policy, London School of Hygiene & Tropical Medicine, London WC1H 9SH, UK.
¹⁰ Department of Pathology, Barts Health NHS Trust, London E1 1FR, UK.
¹¹ North East Thames Regional Genetics Service, Great Ormond Street Hospital, London WC1N 3JH, UK.
¹² Department of Gynaecology, Barking, Havering & Redbridge University Hospitals, Essex RM7 0AG, UK.
¹³ Manchester Centre for Genomic Medicine, Saint Marys Hospital, Manchester M13 9WL, UK.
¹⁴ Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

PMID: 34503154
PMCID: PMC8431198
DOI: 10.3390/cancers13174344

Abstract

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.

Keywords: BRCA; BRIP1; RAD51C; RAD51D; genetic testing; germline; ovarian cancer; somatic.

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Conflict of interest statement

R.M. declares research funding from Barts and the London Charity and Rosetrees Trust outside this work, an honorarium for grant review from Israel National Institute for Health Policy Research and honorarium for advisory board membership from AstraZeneca/MSD/GSK. R.M. is supported by an NHS Innovation Accelerator (NIA) Fellowship for population testing. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. FG declares research funding from The NHS Grampian Endowment Fund, Medtronic and Karl Storz outside this work.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous