Prognostic impact of MAD1L1 promoter hypermethylation in advanced ovarian cancer.

5021 Background: Aberrant methylation of GC-rich gene promoters is a frequent epigenetic event in ovarian cancer leading to silencing of tumor suppressor genes. Identification of methylation biomarkers holds promise for impacting patient survival.,High-throughput screening of hypermethylated CpG islands was conducted by differential methylation hybridization on stage III and IV epithelial ovarian carcinomas. Tumor DNA methylation status was interrogated by methylation-sensitive restriction enzymes, followed by co-hybridization on a custom promoter CpG island array with pooled normal ovarian surface epithelial cell (nOSE) DNA. Microarray findings were validated by quantitative methylation-specific PCR (qMSP) on 55-79 tumor samples.,Methylation levels of 6 novel genes (CYP39A1, EBP, FOXD4b, GTF2A1, MAD1L1 and YY1AP1) functioning in cell cycle control, transcription and drug metabolism/transport were identified as hypermethylated in ovarian cancer versus nOSE (nonparametric Wilcoxon rank sum test, p < 0.005). Using Fisher's exact test, patients with shorter progression-free survival (PFS) (≤18 months) had higher methylation levels compared to those with longer PFS (p = 0.015) for the gene MAD1L1, a mitotic checkpoint protein and antagonist of c-myc that regulates cell proliferation and differentiation. Cox regression analysis of methylation levels and PFS identified a negative correlation for MAD1L1. This correlation achieved statistical significance when MAD1L1 methylation levels combined with chemotherapy response was tested against PFS (p = 0.021), suggesting an interaction of this gene in patient response to chemotherapy.,Induced overexpression of MAD1L1 has been shown to delay cell proliferation and inhibit growth. Downregulation via hypermethylation of this gene results in cell cycle dysregulation, a pathway for disease progression. This epigenetic modification in MAD1L1 renders it a potential target for intervention therapies that could improve patient survival. No significant financial relationships to disclose.