title: Robust BRCA1-like classification of copy number profiles of samples repeated across different datasets and platforms.
abstract: Breast cancers with BRCA1 germline mutation have a characteristic DNA copy number (CN) pattern. We developed a test that assigns CN profiles to be 'BRCA1-like' or 'non-BRCA1-like', which refers to resembling a BRCA1-mutated tumor or resembling a tumor without a BRCA1 mutation, respectively. Approximately one third of the BRCA1-like breast cancers have a BRCA1 mutation, one third has hypermethylation of the BRCA1 promoter and one third has an unknown reason for being BRCA1-like. This classification is indicative of patients' response to high dose alkylating and platinum containing chemotherapy regimens, which targets the inability of BRCA1 deficient cells to repair DNA double strand breaks. We investigated whether this classification can be reliably obtained with next generation sequencing and copy number platforms other than the bacterial artificial chromosome (BAC) array Comparative Genomic Hybridization (aCGH) on which it was originally developed. We investigated samples from 230 breast cancer patients for which a CN profile had been generated on two to five platforms, comprising low coverage CN sequencing, CN extraction from targeted sequencing panels (CopywriteR), Affymetrix SNP6.0, 135K/720K oligonucleotide aCGH, Affymetrix Oncoscan FFPE (MIP) technology, 3K BAC and 32K BAC aCGH. Pairwise comparison of genomic position-mapped profiles from the original aCGH platform and other platforms revealed concordance. For most cases, biological differences between samples exceeded the differences between platforms within one sample. We observed the same classification across different platforms in over 80% of the patients and kappa values of at least 0.36. Differential classification could be attributed to CN profiles that were not strongly associated to one class. In conclusion, we have shown that the genomic regions that define our BRCA1-like classifier are robustly measured by different CN profiling technologies, providing the possibility to retro- and prospectively investigate BRCA1-like classification across a wide range of CN platforms.
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Schouten
authors.affiliation: Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital, King's College London School of Medicine, London, United Kingdom.
authors.forename: Anita
authors.initials: A
authors.lastname: Grigoriadis
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuilman
authors.affiliation: Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital, King's College London School of Medicine, London, United Kingdom.
authors.forename: Hasan
authors.initials: H
authors.lastname: Mirza
authors.affiliation: Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital, King's College London School of Medicine, London, United Kingdom.
authors.forename: Johnathan A
authors.initials: JA
authors.lastname: Watkins
authors.affiliation: Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital, King's College London School of Medicine, London, United Kingdom.
authors.forename: Saskia A
authors.initials: SA
authors.lastname: Cooke
authors.affiliation: Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Ewald
authors.initials: E
authors.lastname: van Dyk
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Tesa M
authors.initials: TM
authors.lastname: Severson
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands; Netherlands Center for Personalized Cancer Treatment, Utrecht, The Netherlands.
authors.forename: Marlous
authors.initials: M
authors.lastname: Hoogstraat
authors.affiliation: Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Caroline V M
authors.initials: CV
authors.lastname: Verhagen
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Esther H
authors.initials: EH
authors.lastname: Lips
authors.affiliation: Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Janneke
authors.initials: J
authors.lastname: Kruizinga
authors.affiliation: Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Arno
authors.initials: A
authors.lastname: Velds
authors.affiliation: Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marja
authors.initials: M
authors.lastname: Nieuwland
authors.affiliation: Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Ron M
authors.initials: RM
authors.lastname: Kerkhoven
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Oscar
authors.initials: O
authors.lastname: Krijgsman
authors.affiliation: Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Conchita
authors.initials: C
authors.lastname: Vens
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Daniel
authors.initials: D
authors.lastname: Peeper
authors.affiliation: Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Petra M
authors.initials: PM
authors.lastname: Nederlof
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK; Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical, Research Centre, Cambridge University Hospitals NHS, Cambridge, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital, King's College London School of Medicine, London, United Kingdom.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Tutt
authors.affiliation: Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands; Faculty of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Delft, The Netherlands.
authors.forename: Lodewyk F
authors.initials: LF
authors.lastname: Wessels
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands; Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: s.linn@nki.nl.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation; D066264:Datasets as Topic; D005260:Female; D018628:Gene Dosage; D019398:Genes, BRCA1; D006801:Humans; D016032:Randomized Controlled Trials as Topic
keywords: BRCA1; Breast cancer; Classification; Copy number aberration profiles
references.citation: J Natl Cancer Inst. 2000 Apr 5;92(7):564-9
references.pmid: 10749912
references.citation: Nucleic Acids Res. 2012 May;40(10):e72
references.pmid: 22323520
references.citation: Biostatistics. 2011 Jul;12(3):413-28
references.pmid: 21209153
references.citation: Cancer Res. 2002 Dec 1;62(23):7110-7
references.pmid: 12460933
references.citation: Nucleic Acids Res. 2005 Nov 28;33(21):e183
references.pmid: 16314297
references.citation: Breast Cancer Res. 2010;12(6):R95
references.pmid: 21080930
references.citation: Bioinformatics. 2008 Mar 15;24(6):759-67
references.pmid: 18204055
references.citation: Nature. 2012 Sep 6;489(7414):57-74
references.pmid: 22955616
references.citation: J Biomol Tech. 2009 Apr;20(2):135-51
references.pmid: 19503625
references.citation: Annu Rev Pathol. 2009;4:461-87
references.pmid: 18954285
references.citation: Nat Rev Cancer. 2004 Oct;4(10):814-9
references.pmid: 15510162
references.citation: Cancer Res. 1997 Apr 1;57(7):1222-7
references.pmid: 9102202
references.citation: BMC Genomics. 2007 Mar 29;8:84
references.pmid: 17394638
references.citation: Genes Chromosomes Cancer. 2011 Feb;50(2):71-81
references.pmid: 21104783
references.citation: Nature. 2012 Apr 18;486(7403):346-52
references.pmid: 22522925
references.citation: Bioinformatics. 2009 Jul 15;25(14):1754-60
references.pmid: 19451168
references.citation: Genes Chromosomes Cancer. 2012 Apr;51(4):344-52
references.pmid: 22162309
references.citation: Mol Oncol. 2015 Aug;9(7):1274-86
references.pmid: 25825120
references.citation: Genome Biol. 2015 Feb 27;16:49
references.pmid: 25887352
references.citation: Nat Protoc. 2011 Nov 03;6(12):1870-86
references.pmid: 22051800
references.citation: BMC Genomics. 2012 Nov 04;13:591
references.pmid: 23442169
references.citation: Nature. 2012 Oct 4;490(7418):61-70
references.pmid: 23000897
references.citation: Clin Cancer Res. 2012 Feb 1;18(3):688-99
references.pmid: 22173549
references.citation: Clin Cancer Res. 2015 Feb 15;21(4):763-70
references.pmid: 25480832
references.citation: Genes Chromosomes Cancer. 2008 Nov;47(11):994-1004
references.pmid: 18663753
references.citation: PLoS One. 2014 Aug 01;9(8):e103177
references.pmid: 25083859
references.citation: Cell Mol Life Sci. 2012 Jan;69(2):223-45
references.pmid: 21922196
references.citation: N Engl J Med. 2003 Jul 3;349(1):7-16
references.pmid: 12840087
references.citation: Ann Oncol. 2011 Jul;22(7):1561-1570
references.pmid: 21135055
references.citation: Clin Cancer Res. 2005 Feb 1;11(3):1146-53
references.pmid: 15709182
references.citation: Clin Cancer Res. 2009 Apr 15;15(8):2711-22
references.pmid: 19318498
references.citation: BMC Genomics. 2009 Dec 08;10:588
references.pmid: 19995423
references.citation: Breast Cancer Res Treat. 2012 Apr;132(2):379-89
references.pmid: 20614180
references.citation: J Pathol. 2014 Apr;232(5):553-65
references.pmid: 24395524
references.citation: Breast Cancer Res Treat. 2013 Jun;139(2):317-27
references.pmid: 23670131
references.citation: BMC Genomics. 2008 Aug 08;9:379
references.pmid: 18691401
references.citation: Breast Cancer Res Treat. 2009 Aug;116(3):479-89
references.pmid: 18704682
references.citation: BMC Cancer. 2007 Mar 07;7:43
references.pmid: 17343727
references.citation: Bioinformatics. 2007 Mar 15;23(6):657-63
references.pmid: 17234643
references.citation: Ann Oncol. 2011 Apr;22(4):870-876
references.pmid: 20937646