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  Wuntakal; Asma  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

doi:10.3390/cancers13174344

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 Wuntakal

Asma 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^* (Corresponding Author)

^*Corresponding author for this work

Queen Mary University of London
Barts Health NHS Trust
University Medical Centre Maribor
University of Hertfordshire
Sechenov First Moscow State Medical University
Barking, Havering and Redbridge University Hospitals NHS Trust
Great Ormond Street Hospital for Children NHS Trust
Tata Institute of Fundamental Research
Saint Marys Hospital
London School of Hygiene and Tropical Medicine
University College London

Research output: Contribution to journal › Article › peer-review

49 Citations (Scopus)

15 Downloads (Pure)

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.

Original language	English
Article number	4344
Number of pages	17
Journal	Cancers
Volume	13
Issue number	17
Early online date	27 Aug 2021
DOIs	https://doi.org/10.3390/cancers13174344
Publication status	Published - Sept 2021
Externally published	Yes

Bibliographical note

Acknowledgments: D.G.E. is supported by the Manchester NIHR Biomedical Research Centre (IS- BRC-1215-20007). OB thanks the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Center „Digital biodesign and personalized healthcare” 075-15-2020-926.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, R.M., upon reasonable request.

Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/cancers13174344/s1, Table S1: List of variants identified through germline and somatic testing.

Funding

The study is funded by The Barts Charity, grant ECMG1B6R. D.G.E. is supported by the Manchester NIHR Biomedical Research Centre (IS- BRC-1215-20007).

Funders	Funder number
The Barts Charity	ECMG1B6R
National Institute for Health and Care Research	IS- BRC-1215-20007

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ovarian cancer
BRCA
genetic testing
germline
somatic
RAD51C
RAD51D
BRIP1

Access to Document

10.3390/cancers13174344Licence: CC BY

Chandrasekaran_etal_Implementation_of_multigene_VOR
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
Final published version, 303 KBLicence: CC BY
Chandrasekaran_etal_supplementary_materialSupplementary Data, 201 KBLicence: Unspecified

Cite this

Chandrasekaran, D., Sobocan, M., Blyuss, O., Miller, R. E., Evans, O., Crusz, S. M., Mills-Baldock, T., Sun, L., Hammond , R. F. L., Gaba, F., Jenkins, L. A., Ahmed, M., Kumar, A., Jeyarajah, A., Lawrence, A. C., Brockbank, E., Phadnis, S., Quigley, M., El Khouly, F., ... Manchanda, R. (2021). Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study. Cancers, 13(17), Article 4344. https://doi.org/10.3390/cancers13174344

Chandrasekaran, D, Sobocan, M, Blyuss, O, Miller, RE, Evans, O, Crusz, SM, Mills-Baldock, T, Sun, L, Hammond , RFL, Gaba, F, Jenkins, LA, Ahmed, M, Kumar, A, Jeyarajah, A, Lawrence, AC, Brockbank, E, Phadnis, S, Quigley, M, El Khouly, F, Wuntakal, R, Faruqi, A, Trevisan, G, Casey, L, Burghel, GJ, Schlecht, H, Bulman, M, Smith, P, Bowers, NL, Legood, R, Lockley, M, Wallace, A, Singh, N, Gareth Evans, D & Manchanda, R 2021, 'Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study', Cancers, vol. 13, no. 17, 4344. https://doi.org/10.3390/cancers13174344

@article{9ae18f3d72c04a7db65b568a426cb5cb,

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

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{\textendash}62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51{\textendash}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 = "ovarian cancer, BRCA, genetic testing, germline, somatic, RAD51C, RAD51D, BRIP1",

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

note = "Acknowledgments: D.G.E. is supported by the Manchester NIHR Biomedical Research Centre (IS- BRC-1215-20007). OB thanks the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Center „Digital biodesign and personalized healthcare{\textquotedblright} 075-15-2020-926.",

year = "2021",

month = sep,

doi = "10.3390/cancers13174344",

language = "English",

volume = "13",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "17",

}

TY - JOUR

T1 - Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer

T2 - SIGNPOST Study

AU - Chandrasekaran, Dhivya

AU - Sobocan, Monika

AU - Blyuss, Oleg

AU - Miller, Rowan E.

AU - Evans, Olivia

AU - Crusz, Shanthini M.

AU - Mills-Baldock, Tina

AU - Sun, Li

AU - Hammond , Rory F. L.

AU - Gaba, Faiza

AU - Jenkins, Lucy A.

AU - Ahmed, Munaza

AU - Kumar, Ajith

AU - Jeyarajah, Arjun

AU - Lawrence, Alexandra C.

AU - Brockbank, Elly

AU - Phadnis, Saurabh

AU - Quigley, Mary

AU - El Khouly, Fatima

AU - Wuntakal, Rekha

AU - Faruqi, Asma

AU - Trevisan, Giorgia

AU - Casey, Laura

AU - Burghel, George J.

AU - Schlecht, Helene

AU - Bulman, Michael

AU - Smith, Philip

AU - Bowers, Naomi L.

AU - Legood, Rosa

AU - Lockley, Michelle

AU - Wallace, Andrew

AU - Singh, Naveena

AU - Gareth Evans, D

AU - Manchanda, Ranjit

N1 - Acknowledgments: D.G.E. is supported by the Manchester NIHR Biomedical Research Centre (IS- BRC-1215-20007). OB thanks the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Center „Digital biodesign and personalized healthcare” 075-15-2020-926.

PY - 2021/9

Y1 - 2021/9

N2 - 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.

AB - 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.

KW - ovarian cancer

KW - BRCA

KW - genetic testing

KW - germline

KW - somatic

KW - RAD51C

KW - RAD51D

KW - BRIP1

U2 - 10.3390/cancers13174344

DO - 10.3390/cancers13174344

M3 - Article

SN - 2072-6694

VL - 13

JO - Cancers

JF - Cancers

IS - 17

M1 - 4344

ER -

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

Abstract

Bibliographical note

Data Availability Statement

Funding

UN SDGs

Keywords

Access to Document

Fingerprint

Cite this