title: A tumor DNA complex aberration index is an independent predictor of survival in breast and ovarian cancer.
abstract: Complex focal chromosomal rearrangements in cancer genomes, also called "firestorms", can be scored from DNA copy number data. The complex arm-wise aberration index (CAAI) is a score that captures DNA copy number alterations that appear as focal complex events in tumors, and has potential prognostic value in breast cancer. This study aimed to validate this DNA-based prognostic index in breast cancer and test for the first time its potential prognostic value in ovarian cancer. Copy number alteration (CNA) data from 1950 breast carcinomas (METABRIC cohort) and 508 high-grade serous ovarian carcinomas (TCGA dataset) were analyzed. Cases were classified as CAAI positive if at least one complex focal event was scored. Complex alterations were frequently localized on chromosome 8p (n = 159), 17q (n = 176) and 11q (n = 251). CAAI events on 11q were most frequent in estrogen receptor positive (ER+) cases and on 17q in estrogen receptor negative (ER-) cases. We found only a modest correlation between CAAI and the overall rate of genomic instability (GII) and number of breakpoints (r = 0.27 and r = 0.42, p < 0.001). Breast cancer specific survival (BCSS), overall survival (OS) and ovarian cancer progression free survival (PFS) were used as clinical end points in Cox proportional hazard model survival analyses. CAAI positive breast cancers (43%) had higher mortality: hazard ratio (HR) of 1.94 (95%CI, 1.62-2.32) for BCSS, and of 1.49 (95%CI, 1.30-1.71) for OS. Representations of the 70-gene and the 21-gene predictors were compared with CAAI in multivariable models and CAAI was independently significant with a Cox adjusted HR of 1.56 (95%CI, 1.23-1.99) for ER+ and 1.55 (95%CI, 1.11-2.18) for ER- disease. None of the expression-based predictors were prognostic in the ER- subset. We found that a model including CAAI and the two expression-based prognostic signatures outperformed a model including the 21-gene and 70-gene signatures but excluding CAAI. Inclusion of CAAI in the clinical prognostication tool PREDICT significantly improved its performance. CAAI positive ovarian cancers (52%) also had worse prognosis: HRs of 1.3 (95%CI, 1.1-1.7) for PFS and 1.3 (95%CI, 1.1-1.6) for OS. This study validates CAAI as an independent predictor of survival in both ER+ and ER- breast cancer and reveals a significant prognostic value for CAAI in high-grade serous ovarian cancer.
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway; Department of Oncology, Division for Surgery, Cancer and Transplantation, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway.
authors.forename: Hans Kristian Moen
authors.initials: HK
authors.lastname: Vollan
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Curtis
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, British Colombia V6T 2B5, Canada; Molecular Oncology, British Colombia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Gulisa
authors.initials: G
authors.lastname: Turashvili
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, British Colombia V6T 2B5, Canada; Molecular Oncology, British Colombia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Sohrab
authors.initials: S
authors.lastname: Shah
authors.affiliation: The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway; Biomedical Informatics Division, Department of Computer Science, University of Oslo, Oslo, Norway; Center for Cancer Biomedicine, University of Oslo, Norway.
authors.forename: Ole Christian
authors.initials: OC
authors.lastname: Lingjærde
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, 237 Fulham Road, SW3 6JB, London, UK.
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Charlotte K
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dunning
authors.affiliation: Strangeways Research Laboratories, University of Cambridge, Cambridge CB1 9RN, UK.
authors.forename: Ed
authors.initials: E
authors.lastname: Dicks
authors.affiliation: Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK; Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Provenzano
authors.affiliation: Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Sammut
authors.affiliation: Molecular Oncology, British Colombia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: McKinney
authors.affiliation: Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG5 1PB, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: King's College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK; NIHR Comprehensive Biomedical Research Centre at Guy's and St. Thomas NHS Foundation Trust and King's College London, London WC2R 2LS, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pinder
authors.affiliation: King's College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK; NIHR Comprehensive Biomedical Research Centre at Guy's and St. Thomas NHS Foundation Trust and King's College London, London WC2R 2LS, UK.
authors.forename: Arnie
authors.initials: A
authors.lastname: Purushotham
authors.affiliation: Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Manitoba R3E 0V9, Canada.
authors.forename: Leigh C
authors.initials: LC
authors.lastname: Murphy
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Medical Division, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK; Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK; Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
authors.affiliation: Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK; Strangeways Research Laboratories, University of Cambridge, Cambridge CB1 9RN, UK; Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK; Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, British Colombia V6T 2B5, Canada; Molecular Oncology, British Colombia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada. Electronic address: saparicio@bccrc.ca.
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK; Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK; Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK. Electronic address: carlos.caldas@cruk.cam.ac.uk.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015996:Survival Rate
chemical_list: D004273:DNA, Neoplasm
keywords: Biomarker; Breast cancer; DNA copy number; Genomic instability; Genomics; Ovarian cancer; Prognostic markers