GSE75414
Epigenetic regulation of the homeobox gene MSX1 associates with platinum resistant disease in high grade serous epithelial ovarian cancer
Introduction: Although High Grade Serous Ovarian Cancer (HGSOC) is considered a chemo-responsive disease, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival of <6 months. Validated biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of resistance. Methods: Differential DNA methylation was investigated in independent tumour sets using Illumina 27K HumanMethylation arrays and validated by bisulphite pyrosequencing. Gene expression was by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction into ovarian cancer cell lines. Results: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in HGSOC which recur by 6 months compared to after 12 months and/or with RECIST response (p<0.05, q<0.05). A decrease in methylation at these intragenic CpG sites was significantly correlated with decreased MSX1 gene expression. Low expression of MSX1 was associated with poor progression-free survival independent of known clinical prognostic features (p=0.014). Three mutant or wild-type TP53 expressing ovarian cancer cell lines, resistant to cisplatin, have reduced MSX1 expression compared to matched parental, platinum sensitive, lines. Re-expression of MSX1 in resistant lines led to cisplatin sensitisation, increased apoptosis, increased p21 and BAX expression. However, in two TP53-null cell lines, MSX1 failed to change cisplatin sensitivity. Conclusion: Hypomethylation of MSX1 is a biomarker of resistant HGSOC disease at presentation and identifies a novel mechanism of platinum drug resistance. Overall design: Bisulphite converted DNA from the 86 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2