Unveiling the epigenomic mechanisms of acquired platinum-resistance in high-grade serous ovarian cancer

Romina Silva, Kate Glennon, Michael Metoudi, Bruce Moran, Sofia Salta, Karen Slattery, Ann Treacy, Terri Martin, Jacqui Shaw, Peter Doran, Lydia Lynch, Carmen Jeronimo, Antoinette S. Perry, Donal J. Brennan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Resistance to platinum-based chemotherapy is the major cause of death from high-grade serous ovarian cancer (HGSOC). We hypothesise that detection of specific DNA methylation changes may predict platinum resistance in HGSOC. Using a publicly available “discovery” dataset we examined epigenomic and transcriptomic alterations between primary platinum-sensitive (n = 32) and recurrent acquired drug resistant HGSOC (n = 28) and identified several genes involved in immune and chemoresistance-related pathways. Validation via high-resolution melt analysis of these findings, in cell lines and HGSOC tumours, demonstrated the most consistent changes were observed in three of the genes: APOBEC3A, NKAPL and PDCD1. Plasma samples from an independent HGSOC cohort (n = 17) were analysed using droplet digital PCR. Hypermethylation of NKAPL was detected in 46% and hypomethylation of APOBEC3A in 69% of plasma samples taken from women with relapsed HGSOC (n = 13), with no alterations identified in disease-free patients (n = 4). Following these results, and using a CRISPR-Cas9 approach, we were also able to demonstrate that in vitro NKAPL promoter demethylation increased platinum sensitivity by 15%. Overall, this study demonstrates the importance of aberrant methylation, especially of the NKAPL gene, in acquired platinum resistance in HGSOC.

Original languageEnglish (US)
Pages (from-to)120-132
Number of pages13
JournalInternational Journal of Cancer
Volume153
Issue number1
DOIs
StatePublished - Jul 1 2023
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Keywords

  • acquired drug resistance
  • DNA methylation
  • high-grade serous ovarian cancer
  • liquid biopsy
  • targeted epigenetic editing

Fingerprint

Dive into the research topics of 'Unveiling the epigenomic mechanisms of acquired platinum-resistance in high-grade serous ovarian cancer'. Together they form a unique fingerprint.

Cite this