Epigenetic Regulation of the Homeobox Gene MSX1 Associates with Platinum-Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer.
Epigenetic Regulation of the Homeobox Gene MSX1 Associates with Platinum-Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer.
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DOI：
10.1158/1078-0432.ccr-15-1669
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发表时间：
2016-06-15
期刊：
影响因子：
--
通讯作者：
Brown R
中科院分区：
文献类型：
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作者：
Bonito NA;Borley J;Wilhelm-Benartzi CS;Ghaem-Maghami S;Brown R
虽然高级别浆液性卵巢癌（HGSOC）经常对化疗有反应，但有一部分患者在就诊时对铂类化疗没有反应，或者无进展生存期少于6个月。经过验证的缺乏反应的预测性生物标志物将为这些患者提供替代治疗分层，并确定新的内在耐药机制。我们的目的是鉴定对化疗反应差的DNA甲基化生物标志物，并证明相关基因参与铂药物细胞敏感性。使用Illumina HumanMethylation阵列和Affymetrix阵列和qRT-PCR在独立肿瘤队列中研究DNA甲基化和基因表达。通过基因再导入和siRNA敲低卵巢癌细胞系，研究了Msh同源盒1 （MSX1）在药物敏感性中的作用。在独立队列（n=146）中，6个月复发的HGSOC患者与12个月复发的HGSOC患者相比，MSX1基因中相邻基因组位置的CpG位点的甲基化水平显著降低（p<0.05,q<0.05,n=78）， RECIST反应较差（p<0.05,q<0.05,n=61），并且与无进展生存（PFS）相关。这些CpG位点甲基化的减少与MSX1基因表达的减少有关。MSX1表达与PFS相关（HR 0.92, 95%CI 0.85-0.99,p=0.029,n=309）。顺铂耐药卵巢癌细胞系MSX1表达降低，MSX1过表达导致顺铂致敏、细胞凋亡增加和顺铂诱导的p21表达增加。MSX1基因内CpG位点的低甲基化与出现时的耐药HGSOC疾病有关，并将MSX1的表达确定为赋予铂药物敏感性。
Although High Grade Serous Ovarian Cancer (HGSOC) is frequently chemo-responsive, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival of less than 6 months. Validated predictive biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of intrinsic resistance. Our aim was to identify DNA methylation biomarkers of poor response to chemotherapy and demonstrate involvement of the associated gene in platinum drug cell sensitivity. DNA methylation was investigated in independent tumour cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines. CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in independent cohorts of HGSOC patients which recur by 6 months compared to after 12 months (p<0.05,q<0.05,n=78), have poor RECIST response (p<0.05,q<0.05,n=61) and are associated with progression-free survival (PFS) in an independent cohort (n=146). A decrease in methylation at these CpG sites correlates with decreased MSX1 gene expression. MSX1 expression is associated with PFS (HR 0.92, 95%CI 0.85-0.99,p=0.029,n=309)). Cisplatin resistant ovarian cancer cell lines have reduced MSX1 expression and MSX1 over-expression leads to cisplatin sensitisation, increased apoptosis and increased cisplatin-induced p21 expression. Hypomethylation of CpG sites within the MSX1 gene is associated with resistant HGSOC disease at presentation and identifies expression of MSX1 as conferring platinum drug sensitivity.