Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.
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