determining whether a human subject is suffering from melanoma cancer by determining the methylation level of the estrogen receptor-alpha (ER- alpha ) gene promoter in the acellular DNA sample; treated with a demethylation agent
Inventors
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-7829283-B2
Publication Date
2010-11-09
Expiration Date
Abstract
Methods for diagnosis, prognosis, and treatment of cancer based on the methylation status of the ER-α gene promoter are disclosed. Methylation of the ER-α gene promoter is indicative of cancer and unfavorable prognosis. The cancer can be treated with a demethylation agent.
Core Innovation
The invention provides a framework in which ER- (estrogen receptor-alpha) gene promoter hypermethylation is used as an epigenetic biomarker in melanoma. ER- promoter hypermethylation is described as silencing ER- and as reflecting measurable methylation level differences between disease states. The framework supports diagnosis, prognosis, and prediction of treatment-related outcomes based on whether the ER- gene promoter methylation level is higher than a control methylation level.
The invention measures ER- gene promoter methylation in acellular DNA isolated from serum and in cellular DNA isolated from tumor tissue. It includes determining the methylation level of the ER- gene promoter and comparing it to a control methylation level to determine whether a human subject is suffering from melanoma cancer. Higher methylated ER- frequency in metastatic versus primary melanoma is observed, and methylated ER- detection in serum is associated with disease stage.
The invention further supports prognosis by predicting shorter survival and more advanced tumor progression when the ER- promoter methylation level is higher than a control methylation level. It also describes that pre-biochemotherapy serum methylated ER- independently predicts poor progression-free and overall survival and reduced response to biochemotherapy in AJCC stage IV melanoma patients. In addition, it reports an in vitro basis for treatment strategy concepts in which demethylation with 5-aza and histone deacetylase inhibition with TSA restores ER- mRNA expression and converts methylated MSP peaks to unmethylated after treatment.
Claims Coverage
The provided claim set includes four independent methods, each grounded on a single core inventive comparison: determining the methylation level of the ER- gene promoter in either serum-derived acellular DNA or tumor-derived cellular DNA and comparing it to a control methylation level. Across the independent claims, the inventive features are directed to melanoma diagnosis, survival prediction, and tumor progression prediction in human subjects with melanoma cancer.
Melanoma diagnosis using serum acellular DNA ER- promoter methylation
providing a serum sample from a human subject suspected of having melanoma cancer; isolating an acellular DNA sample from the serum sample; determining the methylation level of the estrogen receptor-alpha (ER-) gene promoter in the acellular DNA sample; and determining that the human subject is suffering from melanoma cancer when the methylation level of the ER- gene promoter in the acellular DNA sample is higher than a control methylation level.
Survival prediction using serum acellular DNA ER- promoter methylation
providing a serum sample from a human subject having melanoma cancer; isolating an acellular DNA sample from the serum sample; determining the methylation level of the ER- gene promoter in the acellular DNA sample; and predicting a shorter survival when the methylation level of the ER- gene promoter in the acellular DNA sample is higher than a control methylation level.
Tumor progression prediction using tumor cellular DNA ER- promoter methylation
providing a melanoma cancer tumor tissue sample of the human subject having melanoma cancer; isolating a cellular DNA sample from the melanoma cancer tumor tissue sample; determining the methylation level of the ER- gene promoter in the cellular DNA sample; and predicting a more advanced tumor progression when the methylation level of the ER- gene promoter in the cellular DNA sample is higher than a control methylation level.
Tumor progression prediction using serum acellular DNA ER- promoter methylation
providing a serum sample from the human subject having melanoma cancer; isolating an acellular DNA sample from the serum sample; determining the methylation level of the ER- gene promoter in the acellular DNA sample; and predicting a more advanced tumor progression when the methylation level of the ER- gene promoter in the acellular DNA sample is higher than a control methylation level.
All independent claims share the same inventive comparison based on ER- gene promoter methylation level being higher than a control methylation level. They cover diagnosis from serum acellular DNA, survival prediction from serum acellular DNA, and tumor progression prediction from either tumor cellular DNA or serum acellular DNA in human subjects having melanoma cancer.
Stated Advantages
Provides a method for determining whether a human subject is suffering from melanoma cancer based on ER- gene promoter methylation in serum acellular DNA.
Predicts shorter survival in a human subject having melanoma cancer when ER- gene promoter methylation is higher than a control methylation level.
Predicts more advanced tumor progression when ER- gene promoter methylation is higher than a control methylation level, using either tumor cellular DNA or serum acellular DNA.
Supports prognosis and prediction of treatment-related outcomes, including predicting reduced response to biochemotherapy when pre-biochemotherapy serum methylated ER- is present.
Documented Applications
Diagnosis of whether a human subject suspected of having melanoma cancer is suffering from melanoma cancer using methylation level of the ER- gene promoter in serum acellular DNA.
Prediction of survival (shorter survival) in a human subject suffering from melanoma cancer based on ER- gene promoter methylation level in serum acellular DNA.
Prediction of tumor progression (more advanced tumor progression) in a human subject having melanoma cancer using ER- gene promoter methylation in tumor cellular DNA.
Prediction of tumor progression (more advanced tumor progression) in a human subject having melanoma cancer using ER- gene promoter methylation in serum acellular DNA.
Prognosis and treatment outcome correlation in AJCC stage IV melanoma patients, including that pre-biochemotherapy serum methylated ER- independently predicts poor progression-free and overall survival and reduced response to biochemotherapy.
Interested in licensing this patent?