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. 2023 Jul 1;153(1):120-132.
doi: 10.1002/ijc.34496. Epub 2023 Mar 20.

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

Romina Silva  1   2   3 , Kate Glennon  4 , Michael Metoudi  2 , Bruce Moran  5 , Sofia Salta  6 , Karen Slattery  7 , Ann Treacy  8 , Terri Martin  9 , Jacqui Shaw  10 , Peter Doran  9 , Lydia Lynch  11   12 , Carmen Jeronimo  6   13 , Antoinette S Perry  1   3 , Donal J Brennan  2   4
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Unveiling the epigenomic mechanisms of acquired platinum-resistance in high-grade serous ovarian cancer

Romina Silva et al. Int J Cancer. .

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.

Keywords: DNA methylation; acquired drug resistance; high-grade serous ovarian cancer; liquid biopsy; targeted epigenetic editing.

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References

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