{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T03:58:34Z","timestamp":1772164714732,"version":"3.50.1"},"reference-count":38,"publisher":"American Association for Cancer Research (AACR)","issue":"6","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.<\/jats:p>\n                  <jats:p>Significance: Defining the temporal order of tumor-driving somatic events is critical for early detection, risk stratification, and the design of chemopreventive therapies. Our combined experimental and computational approach reveal that the loss of wild-type BRCA1 may not be the first event in the majority of BRCA1-associated breast tumors and may not be present in all cancer cells within tumors. Cancer Discov; 2(6); 503\u201311. \u00a92012 AACR.<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 473<\/jats:p>","DOI":"10.1158\/2159-8290.cd-11-0325","type":"journal-article","created":{"date-parts":[[2012,4,10]],"date-time":"2012-04-10T21:05:37Z","timestamp":1334091937000},"page":"503-511","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":122,"title":["Evolutionary Pathways in BRCA1-Associated Breast Tumors"],"prefix":"10.1158","volume":"2","author":[{"given":"Filipe C.","family":"Martins","sequence":"first","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"}]},{"given":"Subhajyoti","family":"De","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"}]},{"given":"Vanessa","family":"Almendro","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"}]},{"given":"Mithat","family":"G\u00f6nen","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"}]},{"given":"So Yeon","family":"Park","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"}]},{"given":"Joanne L.","family":"Blum","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"}]},{"given":"William","family":"Herlihy","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"}]},{"given":"Gabrielle","family":"Ethington","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"}]},{"given":"Stuart J.","family":"Schnitt","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"}]},{"given":"Nadine","family":"Tung","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"}]},{"given":"Judy E.","family":"Garber","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"}]},{"given":"Katharina","family":"Fetten","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"}]},{"given":"Franziska","family":"Michor","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of Pathology, Seoul"},{"name":"Authors' Affiliations: Departments of 1Medical Oncology, 2Biostatistics and Computational Biology, and 3Radiation Oncology, Dana- Farber Cancer Institute; 4Department of Medicine, Brigham and Women's Hospital; Departments of 5Medicine and 6Pathology, Harvard Medical School; 7Department of Biostatistics, Harvard School of Public Health; Departments of 8Pathology and 9Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Obstetrics and Gynaecology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal; 11Gulbenkian Programme for Advanced Medical Education, Portugal; 12King's College, University of Cambridge, Cambridge, United Kingdom; 13Department of Medical Oncology, Hospital Cl\u00ednic, Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain; 14Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York; 15Department of Pathology, Seoul National University College of Medicine, Seoul; 16Department of 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