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TP53 loss initiates chromosomal instability in fallopian tube epithelial cells
Bronder, Daniel Tighe, Anthony Wangsa, D. Zong, D. Meyer, T. J. Wardenaar, R. Minshall, Paul Hirsch, D. Heselmeyer-Haddad, K. Nelson, Louisa
Bronder, Daniel
Tighe, Anthony
Wangsa, D.
Zong, D.
Meyer, T. J.
Wardenaar, R.
Minshall, Paul
Hirsch, D.
Heselmeyer-Haddad, K.
Nelson, Louisa
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Abstract
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 sub-clonal 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.
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Date
2021
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Article
Citation
Bronder D, Tighe A, Wangsa D, Zong D, Meyer TJ, Wardenaar R, et al. TP53 loss initiates chromosomal instability in fallopian tube epithelial cells. Disease Models & Mechanisms. The Company of Biologists; 2021.