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

来源：

INTERNATIONAL JOURNAL OF CANCER | 2023年 / 153卷 / 01期

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

页码：120 / 132

页数：13

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