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However, the origin and dynamics of such abnormalities in human cancer are not known. In this study, we examined centrosomes in Barrett\u2019s esophagus tumorigenesis, a well-characterized multistep pathway of progression, from the premalignant condition to the metastatic disease. This human cancer model allows the study of sequential steps of progression within the same patient and has representative cell lines from all stages of disease. Remarkably, centrosome amplification was detected as early as the premalignant condition and was significantly expanded in dysplasia. It was then present throughout malignant transformation both in adenocarcinoma and metastasis. The early expansion of centrosome amplification correlated with and was dependent on loss of function of the tumor suppressor p53 both through loss of wild-type expression and hotspot mutations. Our work shows that centrosome amplification in human tumorigenesis can occur before transformation, being repressed by p53. These findings suggest centrosome amplification in humans can contribute to tumor initiation and progression.<\/jats:p>","DOI":"10.1083\/jcb.201711191","type":"journal-article","created":{"date-parts":[[2018,5,8]],"date-time":"2018-05-08T08:40:15Z","timestamp":1525768815000},"page":"2353-2363","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":67,"title":["Centrosome amplification arises before neoplasia and increases upon p53 loss in tumorigenesis"],"prefix":"10.1083","volume":"217","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3182-8305","authenticated-orcid":true,"given":"Carla A.M.","family":"Lopes","sequence":"first","affiliation":[{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal 1"},{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal 2"}]},{"given":"Marta","family":"Mesquita","sequence":"additional","affiliation":[{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal 1"},{"name":"Faculdade de Ci\u00eancias da Sa\u00fade, Universidade da Beira Interior, Covilh\u00e3, Portugal 3"}]},{"given":"Ana Isabel","family":"Cunha","sequence":"additional","affiliation":[{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal 1"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8720-8845","authenticated-orcid":true,"given":"Joana","family":"Cardoso","sequence":"additional","affiliation":[{"name":"Ophiomics-Precision Medicine, Lisbon, Portugal 4"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5678-5634","authenticated-orcid":true,"given":"Sara","family":"Carapeta","sequence":"additional","affiliation":[{"name":"Ophiomics-Precision Medicine, Lisbon, Portugal 4"}]},{"given":"C\u00e1tia","family":"Laranjeira","sequence":"additional","affiliation":[{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal 1"}]},{"given":"Ant\u00f3nio E.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal 1"}]},{"given":"Jos\u00e9 B.","family":"Pereira-Leal","sequence":"additional","affiliation":[{"name":"Ophiomics-Precision Medicine, Lisbon, Portugal 4"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7695-974X","authenticated-orcid":true,"given":"Ant\u00f3nio","family":"Dias-Pereira","sequence":"additional","affiliation":[{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal 1"},{"name":"Faculdade de Ci\u00eancias da Sa\u00fade, Universidade da Beira Interior, Covilh\u00e3, Portugal 3"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1987-5598","authenticated-orcid":true,"given":"M\u00f3nica","family":"Bettencourt-Dias","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal 2"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0732-2059","authenticated-orcid":true,"given":"Paula","family":"Chaves","sequence":"additional","affiliation":[{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal 1"},{"name":"Faculdade de Ci\u00eancias da Sa\u00fade, Universidade da Beira Interior, Covilh\u00e3, Portugal 3"}]}],"member":"291","published-online":{"date-parts":[[2018,5,8]]},"reference":[{"key":"2023072315232368100_bib1","volume-title":"AJCC Cancer Staging Manual.","author":"Amin","year":"2010","edition":"Sixth edition"},{"key":"2023072315232368100_bib2","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1126\/science.2144057","article-title":"Suppression of human colorectal carcinoma cell growth by wild-type p53","volume":"249","author":"Baker","year":"1990","journal-title":"Science."},{"key":"2023072315232368100_bib3","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.tig.2011.05.004","article-title":"Centrosomes and cilia in human disease","volume":"27","author":"Bettencourt-Dias","year":"2011","journal-title":"Trends Genet."},{"key":"2023072315232368100_bib4","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/modpathol.3880324","article-title":"p53 gene mutation and protein accumulation during neoplastic progression in Barrett\u2019s esophagus","volume":"14","author":"Bian","year":"2001","journal-title":"Mod. 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