•
•
•
•
Research implicates a network of genes involved in the etiology of cancer, with emphasis on breast and ovarian cancers. Genes such as BRCA1, p53, HER2, CHK2, and Fanconi anemia are each documented as breast and/or ovarian cancer susceptibility genes. Analyses in this lab show that the genes all share a common architectural design in their promoter regions, which would suggest that a sweeping change in the cellular environment could perpetuate a mechanism of aberrant regulation in some or all of these genes during tumor development. Aberrant methylation is a key epigenetic event in inactivating tumor suppressor genes and the importance of this mechanism in tumorigenesis is well supported (Esteller 2000). Detection of this event could signal a predisposition to cancer irrespective of which gene in the network presented as the initial locus of modification, yielding a diagnosis at the earliest possible stage of intervention.
Research implicates a network of genes involved in the etiology of cancer, with emphasis on breast and ovarian cancers. Genes such as BRCA1, p53, HER2, CHK2, and Fanconi anemia are each documented as breast and/or ovarian cancer susceptibility genes. Analyses in this lab show that the genes all share a common architectural design in their promoter regions, which would suggest that a sweeping change in the cellular environment could perpetuate a mechanism of aberrant regulation in some or all of these genes during tumor development. Aberrant methylation is a key epigenetic event in inactivating tumor suppressor genes and the importance of this mechanism in tumorigenesis is well supported (Esteller 2000). Detection of this event could signal a predisposition to cancer irrespective of which gene in the network presented as the initial locus of modification, yielding a diagnosis at the earliest possible stage of intervention.
Knowledge of the methylation profile of a neoplastic phenotype will aid in the identification of specific types of cancer and the genes that serve as prognostic factors, while providing biomarkers for the level of response to chemotherapy and implicating candidate regions to be reactivated by DNA demethylating drugs. Furthermore, if one universal event in a cell initiates the aberrant methylation of genes containing similar promoter architectures, then knowledge of the network of affected genes will help to elucidate that event.
The Genomic Functional Analysis Section has well-established collaborations with biomedical statisticians at Penn State University and practitioners of women’s health at both Magee-Womens Hospital and NCI, which should greatly facilitate the acquisition and interpretation of data. Furthermore, the lab has a strong record of utilizing computational and experimental analyses in a complementary manner.
Reference:
Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 2000 92:564-9.
