Multicenter Study

. 2015 Jan;9(1):115-27.

doi: 10.1016/j.molonc.2014.07.019. Epub 2014 Aug 8.

A tumor DNA complex aberration index is an independent predictor of survival in breast and ovarian cancer

Hans Kristian Moen Vollan¹, Oscar M Rueda², Suet-Feung Chin², Christina Curtis³, Gulisa Turashvili⁴, Sohrab Shah⁴, Ole Christian Lingjærde⁵, Yinyin Yuan⁶, Charlotte K Ng⁷, Mark J Dunning², Ed Dicks⁸, Elena Provenzano⁹, Stephen Sammut¹⁰, Steven McKinney¹¹, Ian O Ellis¹², Sarah Pinder¹³, Arnie Purushotham¹³, Leigh C Murphy¹⁴, Vessela N Kristensen¹⁵; METABRIC Group; James D Brenton¹⁶, Paul D P Pharoah¹⁷, Anne-Lise Børresen-Dale¹⁸, Samuel Aparicio¹⁹, Carlos Caldas²⁰

Collaborators, Affiliations

Collaborators

METABRIC Group:
Carlos Caldas, Samuel Aparicio, James D Brenton, Ian Ellis, David Huntsman, Sarah Pinder, Arnie Purushotham, Leigh Murphy, Carlos Caldas, Samuel Aparicio, Carlos Caldas, Helen Bardwell, Suet-Feung Chin, Christina Curtis, Zhihao Ding, Stefan Gräf, Linda Jones, Bin Liu, Andy G Lynch, Irene Papatheodorou, Stephen J Sammut, Gordon Wishart, Samuel Aparicio, Steven Chia, Karen Gelmon, David Huntsman, Steven McKinney, Caroline Speers, Gulisa Turashvili, Peter Watson, Ian Ellis, Roger Blamey, Andrew Green, Douglas Macmillan, Emad Rakha, Arnie Purushotham, Cheryl Gillett, Anita Grigoriadis, Sarah Pinder, Emanuele di Rinaldis, Andy Tutt, Leigh Murphy, Michelle Parisien, Sandra Troup, Carlos Caldas, Suet-Feung Chin, Derek Chan, Claire Fielding, Ana-Teresa Maia, Sarah McGuire, Michelle Osborne, Sara M Sayalero, Inmaculada Spiteri, James Hadfield, Samuel Aparicio, Gulisa Turashvili, Lynda Bell, Katie Chow, Nadia Gale, David Huntsman, Maria Kovalik, Ying Ng, Leah Prentice, Carlos Caldas, Simon Tavaré, Christina Curtis, Mark J Dunning, Stefan Gräf, Andy G Lynch, Oscar M Rueda, Roslin Russell, Shamith Samarajiwa, Doug Speed, Florian Markowetz, Yinyin Yuan, James D Brenton, Samuel Aparicio, Sohrab P Shah, Ali Bashashati, Gavin Ha, Gholamreza Haffari, Steven McKinney

Affiliations

¹ 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.
² Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
³ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁴ 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.
⁵ 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.
⁶ Division of Molecular Pathology, The Institute of Cancer Research, 237 Fulham Road, SW3 6JB, London, UK.
⁷ Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
⁸ Strangeways Research Laboratories, University of Cambridge, Cambridge CB1 9RN, UK.
⁹ 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.
¹⁰ Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.
¹¹ Molecular Oncology, British Colombia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada.
¹² Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG5 1PB, UK.
¹³ 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.
¹⁴ Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Manitoba R3E 0V9, Canada.
¹⁵ 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.
¹⁶ 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.
¹⁷ 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.
¹⁸ 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.
¹⁹ 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.
²⁰ 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.

PMID: 25169931
PMCID: PMC4286124
DOI: 10.1016/j.molonc.2014.07.019

Multicenter Study

A tumor DNA complex aberration index is an independent predictor of survival in breast and ovarian cancer

Hans Kristian Moen Vollan et al. Mol Oncol. 2015 Jan.

. 2015 Jan;9(1):115-27.

doi: 10.1016/j.molonc.2014.07.019. Epub 2014 Aug 8.

Authors

Collaborators

METABRIC Group:
Carlos Caldas, Samuel Aparicio, James D Brenton, Ian Ellis, David Huntsman, Sarah Pinder, Arnie Purushotham, Leigh Murphy, Carlos Caldas, Samuel Aparicio, Carlos Caldas, Helen Bardwell, Suet-Feung Chin, Christina Curtis, Zhihao Ding, Stefan Gräf, Linda Jones, Bin Liu, Andy G Lynch, Irene Papatheodorou, Stephen J Sammut, Gordon Wishart, Samuel Aparicio, Steven Chia, Karen Gelmon, David Huntsman, Steven McKinney, Caroline Speers, Gulisa Turashvili, Peter Watson, Ian Ellis, Roger Blamey, Andrew Green, Douglas Macmillan, Emad Rakha, Arnie Purushotham, Cheryl Gillett, Anita Grigoriadis, Sarah Pinder, Emanuele di Rinaldis, Andy Tutt, Leigh Murphy, Michelle Parisien, Sandra Troup, Carlos Caldas, Suet-Feung Chin, Derek Chan, Claire Fielding, Ana-Teresa Maia, Sarah McGuire, Michelle Osborne, Sara M Sayalero, Inmaculada Spiteri, James Hadfield, Samuel Aparicio, Gulisa Turashvili, Lynda Bell, Katie Chow, Nadia Gale, David Huntsman, Maria Kovalik, Ying Ng, Leah Prentice, Carlos Caldas, Simon Tavaré, Christina Curtis, Mark J Dunning, Stefan Gräf, Andy G Lynch, Oscar M Rueda, Roslin Russell, Shamith Samarajiwa, Doug Speed, Florian Markowetz, Yinyin Yuan, James D Brenton, Samuel Aparicio, Sohrab P Shah, Ali Bashashati, Gavin Ha, Gholamreza Haffari, Steven McKinney

Affiliations

¹ 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.
² Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
³ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁴ 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.
⁵ 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.
⁶ Division of Molecular Pathology, The Institute of Cancer Research, 237 Fulham Road, SW3 6JB, London, UK.
⁷ Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
⁸ Strangeways Research Laboratories, University of Cambridge, Cambridge CB1 9RN, UK.
⁹ 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.
¹⁰ Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.
¹¹ Molecular Oncology, British Colombia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada.
¹² Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG5 1PB, UK.
¹³ 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.
¹⁴ Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Manitoba R3E 0V9, Canada.
¹⁵ 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.
¹⁶ 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.
¹⁷ 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.
¹⁸ 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.
¹⁹ 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.
²⁰ 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.

PMID: 25169931
PMCID: PMC4286124
DOI: 10.1016/j.molonc.2014.07.019

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.

Keywords: Biomarker; Breast cancer; DNA copy number; Genomic instability; Genomics; Ovarian cancer; Prognostic markers.

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Figures

**Figure 1**
Distribution of complex events in breast cancer Hierarchical clustering of the CAAI positive cases is shown in panel A, with CAAI positive events in blue and negative in gray. The distribution of CAAI positive cases in molecular subtypes of breast cancer is shown in B (integrative cluster subtypes) and C (PAM50 subtypes).

**Figure 2**
CAAI and overall Genomic Instability Scatter plot of maximum CAAI score and Genomic Instability Index on the actual (A) and a logarithmic (B) scale, colored by CAAI status. Boxplot of GII in CAAI negative and positive cases, colored by number of breakpoints (C). Scatter plot of maximum CAAI score and the number of DNA breakpoints (D), and on a logarithmic (E) scale, colored by CAAI status. Boxplot of number of DNA breakpoints in CAAI negative and positive cases, colored by GII (F).

**Figure 3**
Kaplan–Meier estimates of outcome in breast cancer In A and B survival estimates for CAAI positive and negative cases are shown for breast cancer specific survival (BCSS) and overall survival (OS) respectively. Outcome for lymph node negative and lymph node positive cases are shown in C and D. E and F shows survival estimates for ER+ and ER− cases.

**Figure 4**
Kaplan–Meier estimates of outcome in ovarian cancer Survival estimates for CAAI positive vs. CAAI negative cases with progression free survival (A) and overall survival (B).

See this image and copyright information in PMC

References

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A tumor DNA complex aberration index is an independent predictor of survival in breast and ovarian cancer

Collaborators

Affiliations

A tumor DNA complex aberration index is an independent predictor of survival in breast and ovarian cancer

Authors

Collaborators

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical