title: Assays for hypermethylation of the BRCA1 gene promoter in tumor cells to predict sensitivity to PARP-inhibitor therapy.
abstract: The breast cancer 1 and 2, early onset (BRCA1 and BRCA2) genes are important for double-strand break repair by homologous recombination. Cells with inactivating mutations of the BRCA1 or BRCA2 tumor suppressor genes show increased sensitivity to Poly-ADP ribose polymerase (PARP)-inhibitors in vitro. Sporadic breast tumors with BRCA1 promoter hypermethylation show a similar phenotype to familial BRCA1 patient tumors termed "BRCAness." Sporadic ovarian tumors with functional inactivation of BRCA1 by hypermethylation will also have the BRCA-deficiency phenocopy. The loss of BRCA1 expression associated with promoter hypermethylation will disrupt BRCA-associated DNA repair and may sensitize tumors to BRCA-directed therapies. Thus, the determination of methylation status of BRCA1 may be an important predictive classifier of response to PARP-inhibitor therapy. The methylation, and thereby functional, status of other genes implicated in the wider BRCA/homologous recombination (HR) pathway may also be relevant to the prediction of response to PARP-inhibitor therapy. Here, we describe the four optimal technologies for assaying the promoter methylation status of BRCA1 and/or other genes.
authors.affiliation: Department of Surgical Oncolog, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Ilsiya
authors.initials: I
authors.lastname: Ibragimova
authors.forename: Paul
authors.initials: P
authors.lastname: Cairns
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D066298:In Vitro Techniques; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors