Abstract
ABSTRACTHigh-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.
Highlights
High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of ovarian cancer, and the deadliest gynaecological malignancy (Bowtell et al, 2015)
Since the fallopian tube epithelium is the likely origin for HGSOC we chose the human FNE1 cell line (Ducie et al, 2017; Merritt et al, 2013)
FNE1 cells are near-diploid and karyotypically stable, as confirmed by single-cell whole genome sequencing and spectral karyotyping (SKY). scWGS showed that the genome is largely disomic, except for monosomies at 9p, 15, and X (Fig. S1C)
Summary
High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of ovarian cancer, and the deadliest gynaecological malignancy (Bowtell et al, 2015). HGSOC is characterised by a relatively low mutational burden at the nucleotide level (Ciriello et al, 2013). HGSOC genomes are characterized by extensive chromosomal copy number aberrations, a consequence of rampant chromosomal instability (CIN) (Cancer Genome Atlas Research Network, 2011; Nelson et al, 2020). HGSOC ranks among the most chromosomally unstable tumour types (Ciriello et al, 2013; Shukla et al, 2020), a characteristic confirmed by recent live cell imaging of established cell lines and patient-derived ex vivo cultures, which revealed an unprecedented level of chromosome segregation errors (Nelson et al, 2020; Tamura et al, 2020)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
