An epigenetic marker panel for screening and prognostic prediction of ovarian cancer

Abstract

Aberrant CpG island hypermethylation is a common finding of cancers, which might be detectable in the tissue or serum of affected patients. We analyzed DNA methylation by methylationspecific polymerase chain reaction of 7 genes, which included secreted frizzled receptor proteins 1, 2, 4, 5 (SFRP1, 2, 4, 5), SRYbox 1 (SOX1), paired box gene 1 (PAX1) and LIM homeobox transcription factor 1, alpha (LMX1A) in primary tumor samples from 126 patients with ovarian cancer, 75 with a benign tumor and 14 with borderline malignancy of an ovarian tumor, and in the serum from 26 patients with ovarian cancer and 20 with a benign tumor. Six of 7 genes had higher methylation rates in patients with ovarian cancer than in borderline malignancy or benign tumor (p < 0.001). The methylation of SFRP1, SFRP2, SOX1 and LMX1A genes correlated with recurrence and overall survival of ovarian cancer patients. Combining the data for SFRP1, SFRP2 and SOX1 genes gave a relative risk for recurrence of 3.19 (p 5 0.013) in patients with at least one gene methylation, and combining the data for SFRP1, SOX1 and LMX1A gave an RR for cancer-related death of 6.09 (p 5 0.010). Methylation analysis of tissues and serum revealed a significant correlation (kappa values, 0.332-0.598) and a highly sensitivity and specificity rates (73.08 and 75%) as a screening marker. In conclusion, promoter hypermethylation of specific genes in critical pathways is common in ovarian cancer and has potential as a prognostic factor and a promising serum marker for early screening. ' 2008 Wiley-Liss, Inc.Key words: epigenetics; CpG islands; ovarian cancer; methylationspecific PCR About 190,000 new cases and 114,000 deaths from ovarian cancer are estimated to occur annually in the world. Ovarian cancer is the second most common gynecological malignancy and the fifth leading cause of cancer-related deaths among women in the United States. 1 Because there are no obvious symptoms in the early stage, 70-75% of patients are diagnosed in the advanced stages, and these patients have a low (<20%) 5-year survival rate. 2,3 Elevated serum concentration of cancer antigen 125 (CA125) is often associated with epithelial ovarian cancer but can also be associated with multiple benign disorders. 4 To be effective for screening, a marker requires high sensitivity for early detection and sufficient specificity to protect patients with false-positive results from unwarranted diagnostic evaluations. The development of useful molecular markers for ovarian cancer screening or prognostic prediction is warranted because of the low survival rate in patients diagnosed in the late stage of the disease.Candidate molecular markers include circulating DNA, RNA, or proteins produced from genetic or epigenetic modifications. As in other human cancers, loss of function of tumor suppressor genes (TSGs) caused by gene mutation, deletion or loss of heterozygosity are well-known genetic changes that induce tumor initiation and progression. However, these do not seem to be the major mechanism of TSG inactivation...

Diagnostic and prognostic value of the methylation status of secreted frizzled-related protein 2 in colorectal cancer

“…Accumulating evidence indicates that SFRP2, an important member of the SFRP family, functions as a negative regulator of the oncogenic Wnt pathway through competing with frizzled membrane-bound receptors [18,19]. In a broad range of malignancies including CRC, epigenetic inactivation of SFRP2 by promoter methylation is frequently detected [17,[20][21][22][23]. Here we demonstrated that SFRP2 hypermethylation mostly frequently occurred in CRC patients, followed by patients with advanced adenomas and hyperplastic polyps.…”

“…e unique structure of SFRPs enables them to bind and sequester Wnt molecules from their cognate frizzled receptors, thus interfering with the Wnt pathway. Loss of SFRP2 expression due to promoter methylation has been frequently observed in many tumors, including colorectal, ovarian, breast, gastric and liver cancers [17,[20][21][22][23]. Several earlier studies have demonstrated that the frequency of SFRP2 promoter methylation in fecal DNA is markedly increased in CRC patients compared with normal healthy controls [24][25], suggesting the SFRP2 hypermethylation in fecal DNA as a potential molecular biomarker of CRC.…”

Quantitative DNA methylation analysis of paired box gene 1 and LIM homeobox transcription factor 1 α genes in cervical cancer

“…These unsatisfactory data indicated that it may be necessary to combine other detection methods to improve accuracy. LMX1A methylation is dysregulated in gastric, bladder, breast, ovarian and pancreatic cancer (55)(56)(57)(58). A study on various types of cancer may provide useful insights into the involvement of LMX1A methylation in tumorigenesis.…”

Biomarkers towards Ovarian Cancer Diagnostics: Present and Future Prospects

“…Combining the data for SFRP1, SFRP2 and SOX1 genes gave a relative risk for recurrence of 3.19 (p=0.013) in patients with at least one gene methylation, and combining the data for SFRP1, SOX1 and LMX1A gave a relative risk for cancerrelated death of 6.09 (p=0.010). The sensitivity and specificity were 73.08 and 75%, respectively, when any one of SOX1, PAX1 and SFRP1 genes showed methylation 62 . Further, a microarray analysis resulted in the identification of 112 highly discriminatory loci possessing a progression-free survival prediction accuracy of 95% in ovarian cancer patients by applying SAM and PAM analysis (Significance and prediction analysis of microarray).…”