{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T20:31:11Z","timestamp":1792096271210,"version":"4.4.0"},"reference-count":80,"publisher":"The Company of Biologists","issue":"11","license":[{"start":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T00:00:00Z","timestamp":1638230400000},"content-version":"vor","delay-in-days":29,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["200932\/Z\/16\/Z"],"award-info":[{"award-number":["200932\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Oxford-Cambridge Scholars Program"},{"name":"International Biomedical Research Alliance"},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"crossref","award":["C1422\/A19842"],"award-info":[{"award-number":["C1422\/A19842"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"crossref","award":["C147\/A25254"],"award-info":[{"award-number":["C147\/A25254"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>High-grade serous ovarian cancer (HGSOC) originates in the fallopian tube epithelium and is characterized by ubiquitous TP53 mutation and extensive chromosomal instability (CIN). However, direct causes of CIN, such as mutations in DNA replication and mitosis genes, are rare in HGSOC. We therefore asked whether oncogenic mutations that are common in HGSOC can indirectly drive CIN in non-transformed human fallopian tube epithelial cells. To model homologous recombination deficient HGSOC, we sequentially mutated TP53 and BRCA1 then overexpressed MYC. Loss of p53 function alone was sufficient to drive the emergence of subclonal karyotype alterations. TP53 mutation also led to global gene expression changes, influencing modules involved in cell cycle commitment, DNA replication, G2\/M checkpoint control and mitotic spindle function. Both transcriptional deregulation and karyotype diversity were exacerbated by loss of BRCA1 function, with whole-genome doubling events observed in independent p53\/BRCA1-deficient lineages. Thus, our observations indicate that loss of the key tumour suppressor TP53 is sufficient to deregulate multiple cell cycle control networks and thereby initiate CIN in pre-malignant fallopian tube epithelial cells.<\/jats:p>\n                  <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/dmm.049001","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T07:45:59Z","timestamp":1632728759000},"source":"Crossref","is-referenced-by-count":33,"title":["<i>TP53<\/i>\n                    loss initiates chromosomal instability in fallopian tube epithelial cells"],"prefix":"10.1242","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1666-2896","authenticated-orcid":false,"given":"Daniel","family":"Bronder","sequence":"first","affiliation":[{"name":"Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research 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