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TP53 loss initiates chromosomal instability in fallopian tube epithelial cells.

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 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. This article has an associated First Person interview with the first author of the paper.

SUBMITTER: Bronder D

PROVIDER: S-EPMC8649171 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TP53 loss initiates chromosomal instability in fallopian tube epithelial cells

Project description:High-grade serous ovarian cancer originates in the fallopian tube and is characterized by ubiquitous mutations in TP53. Here, we generated TP53 single-, TP53/BRCA1 and TP53/MYC double- and TP53/BRCA1/MYC triple-mutant subclones of the fallopian tube-derived cell line FNE1 using CRISPR/Cas9. These mutant subclones were subsequently subjected to RNA sequencing to determine the impact of these oncogenic mutations on signaling pathways.

2021-09-28 | GSE182487 | GEO

TP53 loss initiates chromosomal instability in fallopian tube epithelial cells

Project description:TP53 loss initiates chromosomal instability in fallopian tube epithelial cells

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Molecular requirements for transformation of fallopian tube epithelial cells into serous carcinoma.

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Mucinous adenocarcinoma developed from human fallopian tube epithelial cells through defined genetic modifications.

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