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

被引:7
作者
Silva, Romina [1 ,2 ,3 ]
Glennon, Kate [4 ]
Metoudi, Michael [2 ]
Moran, Bruce [5 ]
Salta, Sofia [6 ]
Slattery, Karen [7 ]
Treacy, Ann [8 ]
Martin, Terri [9 ]
Shaw, Jacqui [10 ]
Doran, Peter [9 ]
Lynch, Lydia [11 ,12 ]
Jeronimo, Carmen [6 ,13 ]
Perry, Antoinette S. [1 ,3 ]
Brennan, Donal J. [2 ,4 ]
机构
[1] Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Canc Biol & Therapeut Lab, Dublin, Ireland
[2] Univ Coll Dublin, Sch Med, Syst Biol Ireland, Dublin, Ireland
[3] Univ Coll Dublin, Sch Biol & Environm Sci, Dublin, Ireland
[4] UCD, Gynaecol Oncol Grp, Mater Misericordiae Univ Hosp, Sch Med, Dublin, Ireland
[5] St Vincents Univ Hosp, Dept Pathol, Dublin, Ireland
[6] IPO Porto Porto Comprehens Canc Ctr Porto CCC, CI IPOP RISECI IPOP Hlth Res Network, Portuguese Oncol Inst Porto, IPO Porto Res Ctr IPO Porto,Canc Biol & Epigenet G, Porto, Portugal
[7] Trinity Coll Dublin, Sch Biochem & Immunol, Dublin, Ireland
[8] Mater Misericordiae Univ Hosp, Dept Pathol, Dublin, Ireland
[9] UCD, Mater Misericordiae Univ Hosp, Clin Res Ctr, Sch Med, Dublin, Ireland
[10] Univ Leicester, Leicester Canc Res Ctr, Leicester, England
[11] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA
[12] Trinity Coll Dublin, Trinity Biomed Sci Inst, Dublin, Ireland
[13] Univ Porto, Inst Biomed Sci Abel Salazar, Dept Pathol & Mol Immunol, ICBAS, Porto, Portugal
基金
爱尔兰科学基金会;
关键词
acquired drug resistance; DNA methylation; high-grade serous ovarian cancer; liquid biopsy; targeted epigenetic editing; SINGLE-CELL DISSECTION; DNA METHYLATION; CISPLATIN RESISTANCE; DCAS9-PEPTIDE REPEAT; PREDICTS; CHEMOTHERAPY; SENSITIVITY; EXPRESSION; SIGNATURES; METHYLOME;
D O I
10.1002/ijc.34496
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:120 / 132
页数:13
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