2015 Keystone Conf: DNA Methylome Alterations in Platinum Resistant Ovarian Cancer Tumors

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Summary

Epigenetic changes, particularly DNA methylation aberrations have been implicated in acquired resistance to platinum in ovarian cancer. An ongoing phase I/II multi-institutional clinical trial uses the novel DNA methyl transferase (DNMT) inhibitor SGI-110 to resensitize recurrent platinum resistant ovarian cancer to carboplatin.

Tumor biopsies or malignant ascites were collected at baseline and after two cycles of SGI-110 administered daily for 5 days in low dose (30mg/m2). The goal of the current study was to analyze
global DNA methylation profiles of platinum resistant tumors and compare them to the methylome of untreated, platinum-sensitive ovarian tumors. LINE1 methylation and promoter methylation of
selected genes (MAGE-A2, MAGE-A3, MAGE-A11, NY-ESO, RASSF1, MLH1, and HOXA11) were quantified by pyrosequencing before and after SGI-110 treatment (n=12 paired samples).

Epigenetic profiling using the Infinium HumanMethylation450 BeadChip (HM450) revealed extensive methylation changes when comparing recurrent platinum resistant ovarian tumors (n=42) to
primary, untreated ovarian cancer specimens analyzed as part of the TCGA project (n=10). Six hundred and four promoters were significantly differentially methylated (adjusted p<0.05, absolute methylation changes β>0.2), among which, 498 and 106 were hypermethylated or hypomethylated respectively in recurrent platinum resistant ovarian tumors. DNMT1, 3A, and 3B mRNA levels in the tumors were highly variable (n=19). Analysis of a limited number of paired samples (n=7) revealed no significant changes in global methylation or in DNMT expression levels induced by  treatment with SGI-110 (adjusted p>0.05). However, the DNMT inhibitor induced significant methylome alterations in selected patients. Significant hypomethylation of MAGE-A3 and
MAGE–A11 promoters (p<0.05) was detected. Correlations between methylation changes and clinical outcomes are being explored.

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2015 Keystone Conf: DNA Methylome Alterations in Platinum Resistant Ovarian Cancer Tumors