This is a Fast-Track proposal to develop a tissue-based genetic test for BRCA1 hereditary ovarian cancer. Ten percent of unselected US ovarian cancers are BRCA1 hereditary cancers with truncating mutations in the BRCA1 gene. It is important to know which ovarian cancer patients have BRCA1 hereditary ovarian cancer because BRCA1 patients have an increased risk of breast cancer and their relatives with mutations have an increased risk of breast and ovarian cancer. These subsequent cancers would be discovered early or prevented if widespread genetic screening was available and recent data indicates that BRCA hereditary cancers respond to targeted therapies such as cis-platinum and PARP inhibitors. We have developed an antibody-based tissue truncation method to identify BRCA1 hereditary cancers and were able to correctly identify 5/5 BRCA1 hereditary cancers and 20/200 sporadic cancers in a pilot study. This approach visualizes protein truncation by showing with immunohistochemistry (IHC) that the N-terminus is present but the C-terminus is absent. The product (test) will be an antibody-based IHC diagnostic kit for cancer tissue samples which hospital labs will use to identify hereditary cancers. We have already successful developed and published a similar IHC method to identify BRCA2 hereditary cancers with sensitivity of 95% and specificity of 98%.The milestones for the Phase I proposal are: 1) Determine optimal tissue preparation protocols for IHC with both N-terminal and C-terminal BRCA1 antibodies. 2) Develop a quantitative scoring system for N-terminal and C-Terminal BRCA1 immunostaining on ovarian tissues with intra-assay variability of 15% and inter-assay variability of 20% or less. 3) Demonstrate that a C-terminal to N-terminal ratio for protein truncation (BRCA1 Truncation Ratio) can distinguish 20 hereditary BRCA1 ovarian cancers from 50 sporadic ovarian cases with greater than 90% sensitivity and specificity (comparing different scoring systems). Upon completion of these milestones we would pursue the following Phase II milestones: Milestone 1a: Determine the specificity of the BRCA1 truncation ratio in 20 ovarian cancers in patients known to have BRCA2 mutations. Milestone 1b: Determine the specificity of the truncation ratio in 10 ovarian cancers in patients reported to have polymorphisms/missense variants of BRCA1. Milestone 2: Determine if the BRCA1 truncation test can achieve 90% sensitivity and specificity in a clinical trial of 300 ovarian cancer samples (sample size to provide 30 BRCA1 hereditary cancers). The medical application of breast/ovarian cancer genetic testing is a proven market since Myriad Genetics annually grosses $150 million on DNA sequencing.
Public Health Relevance: Successful completion of this Fast-track research will establish a new tissue- based genetic test for BRCA1 hereditary ovarian cancer based on an IHC method to visualize protein truncation. This simpler more widely applicable approach will help predict appropriate therapy for patients with BRCA1 hereditary cancer and identify many more families with hereditary breast and ovarian cancer and consequently help patients and their relatives by identifying individuals likely to develop subsequent breast or ovarian cancer which might be prevented by tamoxifen and/or screening.
Thesaurus Terms: "(Sp-4-2)-Diamminedichloroplatinum; (Z)-2-[4(1,2-Diphenyl-1-Butenyl)-Phenoxyl]-N,N-Dimethylethanamine; 1-P-Beta-Dimethylamino-Ethoxyphenyl-Trans-1,2-Diphenylbut-1-Ene; Asco; Address; Affect; Alleles; Allelomorphs; American Society Of Clinical Oncology; Animals; Antibodies; Archives; Area; Artifacts; Assay; Au Element; Authorization; Authorization Documentation; Award; Brca1; Brca1 Gene Product; Brca1 Mutation; Brca1 Protein; Brca1 Gene; Brca2; Brca2 Gene Product; Brca2 Mutation; Brca2 Protein; Brca2 Gene; Base Sequence; Bioassay; Biologic Assays; Biological Assay; Biopsy; Blood; Blood Glucose; Blood Sample; Blood Serum; Blood Sugar; Blood Specimen; Body Tissues; Boston; Breast; Breast Cancer 1 Gene; Breast Cancer 1 Gene Product; Breast Cancer 1, Early Onset Gene; Breast Cancer 1, Early Onset Protein; Breast Cancer 2 Gene; Breast Cancer 2 Gene Product; Breast Cancer 2, Early Onset Gene; Breast Cancer 2, Early Onset Protein; Breast Cancer Type 1 Susceptibility Gene; Breast Cancer Type 1 Susceptibility Protein; Breast Cancer Type 2 Susceptibility Gene; Breast Cancer Type 2 Susceptibility Protein; Breast-Ovarian Cancer Protein; C-Terminal; Cddp; Cancer Patient; Cancer Screening For Patients; Cancer Susceptibility Gene; Cancer Of Breast; Cancer Of The Ovary; Cancer-Predisposing Gene; Cancers; Cell/Tissue, Immunohistochemistry; Cholest-5-En-3-Ol (3beta)-; Cholesterol; Chromatography, High Performance Liquid; Chromatography, High Pressure Liquid; Chromatography, High Speed Liquid; Chromosomes; Cis-Diammine-Dichloroplatinum; Cis-Diamminedichloridoplatinum; Cis-Diamminedichloro Platinum (Ii); Cis-Dichloroammine Platinum (Ii); Cis-Platinous Diamine Dichloride; Cis-Platinum Ii; Cis-Platinum Ii Diamine Dichloride; Cisplatin; Cisplatina; Cisplatinum; City Of Boston; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Colorado; Comment; Comment (Pt); Comment [publication Type]; Commentary; Commentary (Pt); Communities; Companions; Complex; Confidentiality; Cysplatyna; Ddp; Dgge; Dna Alteration; Dna Sequence; Dna Amplification; Dna Mutation; Data; Defect; Development; Development And Research; Diagnosis; Diagnostic; Diagnostic Tests; Dichlorodiammineplatinum; Disadvantaged; Elig; Editorial Comment; Editorial Comment (Pt); Effectiveness; Eligibility; Eligibility Determination; Employee Strikes; Epithelial; Ethanamine, 2-(4-(1,2-Diphenyl-1-Butenyl)Phenoxy)-N,N-Dimethyl-, (Z)-; Exclusion; Exons; Fancb; Fancd1; Fda Approved; Familial Breast Carcinoma; Familial Breast And Ovarian Cancer Syndrome; Familial Cancer Of The Breast; Familial Disease; Familiar Malignant Neoplasm; Family; Family Member; Freedom; Funding; Gene Alteration; Gene Amplification; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic Condition; Genetic Counseling; Genetic Diseases; Genetic Polymorphism; Genetic Screening; Genetic Defect; Genetic Mutation; Genetic Screening Method; Genomics; Glare; Gold; Hosp; Hplc; Health; Hereditary; Hereditary Breast Cancer; Hereditary Breast Cancer 1; Hereditary Breast Cancer 2; Hereditary Breast Carcinoma; Hereditary Breast And Ovarian Cancer; Hereditary Breast And Ovarian Cancer Syndrome; Hereditary Cancer; Hereditary Disease; Hereditary Malignant Neoplasm; Heteroduplex Analyses; Heteroduplex Analysis; High Pressure Liquid Chromatography; Hospitals; Human Genetics; Ihc; Immunohistochemistry; Immunohistochemistry Staining Method; In Vitro; Incidence; Individual; Informed Consent; Inherited; Insurance; Intellectual Property; Internal Medicine; Knowledge; Laboratories; Legal Patent; Liberty; Licensing; Malignant Cell; Malignant Neoplasms; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Tumor; Malignant Tumor Of The Breast; Malignant Tumor Of The Ovary; Malignant Neoplasm Of Breast; Malignant Neoplasm Of Ovary; Marketing; Mass Spectrum; Mass Spectrum Analysis; Medical; Medical Societies; Medical Center; Methods; Methods And Techniques; Methods, Other; Molecular Disease; Morphologic Artifacts; Mutation; Mutation Detection; Mutation Of The Brca1 Gene; Mutation Of The Brca2 Gene; N-Terminal; Nh2-Terminal; Normal Tissue; Normal Tissue Morphology; Nucleotide Sequence; Ovarian; Ovarian Tissue; Pscp; Patents; Patients; Pattern; Penetrance; Peptides; Permission; Peyrone's Chloride; Peyrone's Salt; Phase; Phase I/Ii Trial; Photometry/Spectrum Analysis, Mass; Pilot Projects; Platinum Diamminodichloride; Platinum, Diaminedichloro-, Cis- (8ci); Platinum, Diamminedichloro-, (Sp-4-2)-; Polymorphism (Genetics); Polymorphism, Genetic; Population; Predictive Value; Prevention; Prevention Strategy; Preventive; Preventive Strategy; Privacy; Process; Protein Truncation; Proteins; Proteomics; Protocol; Protocol Screening; Protocols Documentation; Published Comment; Publishing; R & D; R&D; Rnf53; Reading; Relative; Relative (Related Person); Reporting; Research; Resolution; Reticuloendothelial System, Blood; Risk; Sbir; Sbirs (R43/44); Sscp; Sample Size; Sampling; Screening For Ovarian Cancer; Screening For Cancer; Screening Procedure; Sensitivity And Specificity; Sequence Alteration; Serum; Single-Stranded Conformational Polymorphism; Small Business Innovation Research; Small Business Innovation Research Grant; Specificity; Spectrometry, Mass; Spectroscopy, Mass; Spectrum Analyses, Mass; Spectrum Analysis, Mass; Staining Method; Stainings; Stains; Strikes; Strikes, Employee; System; System, Loinc Axis 4; Tam; Tamoxifen; Techniques; Technology; Testing; Time; Tissue Sample; Tissues; Translations; Universities; Variant; Variation; Viewpoint; Viewpoint (Pt); Anticancer Research; Base; Brca 1 Gene; Brca 2 Gene; Cancer Cell; Cancer Genetics; Cancer Research; Cancer Risk; Cis Dichlorodiammineplatinum; Cis Platinum Compound; Cis-Diaminedichloroplatinum; Cis-Diamminedichloroplatinum; Cis-Diamminedichloroplatinum(Ii); Cis-Dichlorodiammineplatinum(Ii); Cis-Platinum; Clinical Investigation; Commercialization; Cost; Cost Effective; Denaturing Gradient Gel Electrophoresis; Early Cancer Detection; Experiment; Experimental Research; Experimental Study; Familial Cancer; Familial Disorder; Gene Expression Signature; Gene Product; Genetic Disorder; Genetic Testing; Genome Mutation; Hereditary Disorder; High Risk; Improved; Inhibitor; Inhibitor/Antagonist; Malignancy; Malignant Breast Neoplasm; Mutant; Mutation Carrier; Natural Gene Amplification; Neoplasm/Cancer; New Approaches; Novel; Novel Approaches; Novel Strategies; Novel Strategy; Nucleic Acid Sequence; Ovarian Cancer; Ovarian Cancer Detection; Ovarian Cancer Early Detection; Ovarian Cancer Early Screening; Peripheral Blood; Pilot Study; Polymorphism; Prevent; Preventing; Privacy Of Information; Public Health Relevance; Research And Development; Research Study; Screening; Screenings; Single Strand Conformation Polymorphism; Technological Innovation; Tissue Preparation; Transcriptome; Treatment Strategy; Tumor"
