Prognostic impact of MAD1L1 promoter hypermethylation in advanced ovarian cancer

Autor: Joseph Liu, P. S. Van, David E. Cohn, Robert S. Brown, Tim H M Huang, Rachel A. Jansen, van der Ate Zee, Sandya Liyanarachchi, Anne P G Crijns, J. M. Fowler
Rok vydání: 2006
Předmět:
Zdroj: Journal of Clinical Oncology. 24:5021-5021
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2006.24.18_suppl.5021
Popis: 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. Methods: 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. Results: 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. Conclusions: 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.
Databáze: OpenAIRE
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