Funded Projects 2001
Grant Number: 001/2001
PI Name: Mirhashemi, Ramin and Arena, J. Fernando
Project Title: Pharmacogenomics Approach to Predict Chemotherapeutic Response to Ovarian Cancer Treatment.
Abstract: DESCRIPTION: (Adapted from investigator's abstract)
The goal of this project is to identify, qualify and quantify the genetic and environmental determinants of human variability in Ovarian Cancer chemotherapy response. To do this, we will explore the connection between human genetic variation (polymorphism), extrinsic factors (environment) and treatment response (phenotype) using state-of-the-art automated genomics equipment and genetic algorithms. Specifically, we will build a relational database containing patient genotype, phenotype and environmental data in order to "mine" statistically relevant associations and patterns using novel mathematical techniques. The specific drugs whose efficacy we will investigate are Adriamycin, Taxol, Topotecan and Thalidomide.
Of the many steps we will take in this project, the first is to identify novel SNP/Haplotypes for genes of suspected import to Ovarian Cancer chemotherapy. These genes include xenobiotic metabolism and basic cellular housekeeping genes such as tubulins and topoisomerases. For novel SNP/Haplotype discovery, we will use a relatively small (approx. 50) patient cohort. Entire regions of genes will be sequenced for these patients, and new SNPs discovered by comparing the sequences. New haplotypes for these SNPs and genes in the population will be documented. The genes that we will perform this for genes whose known functionality lend them as good candidates as modulators of chemotherapeutic drug efficacy. This particular phase of the study will address inadequacies with the current public human genome variation database (dbSNP). Since the public databaese relies on limited numbers of donors, who are generally healthy, it is necessarily biased against causative or etiologically relevant variants for most human afflictions. We will also mine the public human genome databases for known and undiscovered SNPs. All data mining for new SNPs will utilize a proprietary data mining software package developed at DNAprint genomics. The database of SNP locations and Haplotypes that results will contribute to a sort of "road map" which offers the opportunity to gain unique and valuable insight into Ovarian Cancer. This "road map" will serve as a guide by which the high-throughput experiments will be conducted.
The second step in our project will be to score these novel SNPs and Haplotypes in large patient cohorts. We will use the "road map" of SNP/HAP variability data with a larger study cohort (several hundreds of patients) to score genotypes in several hundred genes. SNPs and haplotypes will be scored using an automated genotyping platform and proprietary inferential informatics.
In addition to genotypes, matching biographical information such as drug dosage, response, environmental and other information will be collected and added to the relational database. This database will then be mined for associations using various mathematical techniques that consider sources of pattern on multiple levels of genetic complexity. Methodology types that will be used include geometric modeling, bayesian clustering, and artificial intelligence such as neural networks. Methodologies will incorporate various encoding schemes and genetic parameters, produced from the application of proprietary genetic algorithms and genetic grouping variables. Haplotype and sub-haplotype patterns will be investigated using pair-wise linkage disequilibria. New methods for improving the detection power for three-way and even four-way linkage disequilibria will be explored. Haplotypes will be inferred from genotype data. If successful, the project will culminate in the publication, patenting and commercialization of our results, which may eventually lead to a new diagnomics product that can be used with personal genetic information to guide patient chemotherapy treatment decisions.
Institution: UNIVERSITY OF MIAMI
1475 N. W. 12TH AVE.
MIAMI, FL 33136
Fiscal Year: 2001
Department: OB/GYN
Project Start: 01-January, 2001
Project End: 31-December, 2002
FUNDING AGENCY DNA PRINT GENOMICS
Address: DNAPrint genomics, Inc.900 Cocoanut Ave.Sarasota, FL 34236941-366-3400941-952-9770 fax
Grant Number: 002/2001
PI Name: Arena, J. Fernando
Project Title: Development of a BRCA1 and BRCA2 mutation screening assay for women of African descent.
Abstract: DESCRIPTION: (Adapted from investigator's abstract)
The long term objective of this application is to develop and to clinically validate a screening panel for specific BRCA1 and BRCA2 mutation/genetic variants in women of African descent with breast cancer. The development of such panel will allow its incorporation into clinical practice with clear improvement of genetic counseling for this minority population. African-American women under age 50 in the United States have the highest rate of new cases of breast cancer in the nation. In addition, African-American women of all ages have a larger percentage of poorly differentiated breast cancer, that is more likely to occur at an earlier age and to be estrogen and progesterone receptor negative - all factors associated with more aggressive tumorgenicity. Based on this preliminary data and a thorough review of all published English literature, we have identified thirteen mutations and thirteen unclassified variants in BRCA1 and six mutations and ten variants in BRCA2. A screening panel for such BRCA1 and BRCA2 mutations/variants will be designed to develop an efficient assay for eventual use in clinical practice. This assay is based on a combination of multiplex PCR and multiplex SSCP in order to provide a high throughput screening method for the above designated genetic alterations. SSCP variants will be further investigated by DNA sequencing to confirm the exact genetic change. The development of this screening panel will have an important impact on genetic counseling for women of African descent. It may also be helpful in anticipating the design of preventive strategies (mammography, chemoprevention, or prophylactic surgery) and in selecting appropriate therapeutic protocols for this underserved and under investigated patient population.
Institution: UNIVERSITY OF MIAMI
1475 N. W. 12TH AVE.
MIAMI, FL 33136
Fiscal Year: 2001
Department: OB/GYN
Project Start: 01-January, 2002
Project End: 31-December, 2003
FUNDING AGENCY Sylvester Comprehensive Cancer Center
Address: 1475 N.W. 12th Miami Fl, 33136
