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An evaluation of the challenges to developing tumour BRCA1 and BRCA2 testing methodologies for clinical practice.

  • Ellison, Gillian1
  • Ahdesmäki, Miika2
  • Luke, Sally3
  • Waring, Paul M4
  • Wallace, Andrew5
  • Wright, Ronnie5
  • Röthlisberger, Benno6
  • Ludin, Katja6
  • Merkelbach-Bruse, Sabine7
  • Heydt, Carina7
  • Ligtenberg, Marjolijn J L8, 9
  • Mensenkamp, Arjen R8
  • Castro, David Gonzalez10, 11
  • Jones, Thomas11
  • Vivancos, Ana12
  • Kondrashova, Olga4
  • Pauwels, Patrick13
  • Weyn, Christine13
  • Hahnen, Eric14
  • Hauke, Jan14
  • And 7 more
  • 1 Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Macclesfield, UK.
  • 2 Translational Science, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
  • 3 R&D Information, AstraZeneca, Cambridge, UK.
  • 4 Department of Pathology, University of Melbourne, Parkville, Melbourne, Victoria, Australia. , (Australia)
  • 5 Genomic Diagnostics Laboratory, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, Manchester, UK.
  • 6 Kantonsspital Aarau, Institut für Labormedizin, Abteilung für Medizinische Genetik, Aarau, Switzerland. , (Switzerland)
  • 7 Institute of Pathology, University Hospital Cologne, Cologne, Germany. , (Germany)
  • 8 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. , (Netherlands)
  • 9 Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. , (Netherlands)
  • 10 Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
  • 11 The Centre for Molecular Pathology, The Royal Marsden NHS FT, Sutton, UK.
  • 12 Laboratory 2.01, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. , (Spain)
  • 13 Center for Oncological Research (CORE), Pathology Department, University Hospital Antwerp (UZA), Edegem, Belgium. , (Belgium)
  • 14 Center for Hereditary Breast and Ovarian Cancer and Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany. , (Germany)
  • 15 Cancer Science Institute of Singapore, and Department of Pathology, National University of Singapore, Singapore, Singapore. , (Singapore)
  • 16 Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, IMED Oncology, Waltham, MA, USA.
  • 17 Translational Science, Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, USA.
Published Article
Human Mutation
Wiley (John Wiley & Sons)
Publication Date
Dec 07, 2017
DOI: 10.1002/humu.23375
PMID: 29215764


Ovarian cancer patients with germline or somatic pathogenic variants benefit from treatment with PARP inhibitors. Tumour BRCA1/2 testing is more challenging than germline testing as the majority of samples are formalin fixed paraffin embedded (FFPE), the tumour genome is complex and the allelic fraction of somatic variants can be low. We collaborated with 10 laboratories testing BRCA1/2 in tumours to compare different approaches to identify clinically important variants within FFPE tumour DNA samples. This was not a proficiency study but an inter-laboratory comparison to identify common issues. Each laboratory received the same tumour DNA samples ranging in genotype, quantity, quality and variant allele frequency (VAF). Each lab performed their preferred Next Generation Sequencing method to report on the variants. No false positive results were reported in this small study and the majority of methods detected the low VAF variants. A number of variants were not detected due to the bioinformatics analysis, variant classification or insufficient DNA. The use of hybridisation capture or short amplicon methods are recommended based on a bioinformatic assessment of the data. The study highlights the importance of establishing standards and standardisation for tBRCA testing particularly when the test results dictate clinical decisions regarding life extending therapies. This article is protected by copyright. All rights reserved.

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