Research Program Overview
The major focus in the laboratory is molecular oncology and the investigation of molecular genetic changes associated with women's cancers, both inherited and acquired. A subset of ovarian cancer patients is considered to have a hereditary predisposition. The BRCA1 and BRCA2 genes are implicated in the hereditary breast-ovarian cancer syndrome. The primary approach has included surveys of somatic genetic alterations in tumors, and positional cloning and characterization of tumor suppressor and growth regulatory genes.
Hereditary Breast Cancer and Novel Hispanic BRCA Mutations
We are obtaining a comprehensive dataset on the prevalence and nature of BRCA mutations among Hispanics. We documented that the Jewish founder mutation, BRCA1 185delAG, is prevalent in Hispanic populations; we discovered a novel BRCA1 rearrangement, the result of an Alu repeat-mediated recombination event, that accounts for a substantial proportion of high-risk Hispanic families. We are developing and testing the clinical effectiveness of a panel of recurrent BRCA mutations on the Sequenom (mass spectroscopy) high throughput platform for prospective screening of high-risk clinic cohorts, supported in part by an NCI R03 grant (3/1/09) for the project. This will represent the largest series of Hispanics with BRCA mutation information and clinical annotation.
Markel Ovarian Cancer Research Program
This project has three main focuses: 1)The development of new tools and enhanced prediction models to identify women at increased risk of ovarian cancer in order to facilitate prevention and early detection; 2) Linking molecular diagnostics to molecular therapeutics to permit individualized therapy through enhanced recruitment infrastructure of clinical trials for BRCA carriers; 3) Examining outcomes of initial therapy for women with BRCA-associated ovarian cancer and looking for genotype/phenotype correlations that may shed light on mechanisms of acquired resistance to therapy.
Molecular Genetic Studies of Cancer Patients and Their Relatives
A key resource in the lab is our prospective hereditary cancer registry, which includes biospecimens (more than 7,000 samples to date) for investigating factors that may contribute to the development of specific cancers in cancer patients and/or their relatives. The registry includes one of the largest existing sets of BRCA1/2 carriers (>600 families) at a single institution. Data and biospecimens from the registry also enable participation in the multi-institutional consortia that are necessary to assemble enough hereditary cases for epidemiological studies. We demonstrated remarkable concordance for hormone collaborative receptor status in BRCA1/2 carriers with bilateral breast cancer (CEBP, 2005. 14: 1534-8). BRCA modifier gene studies are also being conducted.
Breast Cancer Research Foundation
Recently, Angelina Jolie refocused attention on hereditary breast cancer risk and difficult choices available to prevent the disease, 17 years after commercial BRCA testing became available in the U.S. However, access to BRCA gene testing and genetic counseling, long a standard of care in most developed countries, is not available in the majority of Latin America and Mexico. Our preliminary studies of 746 U.S. Hispanics documented BRCA mutations in 189 (25%) women. The pattern of mutations was not random. Rather, many mutations were recurrent, seen in multiple unrelated families. Most of these mutations appear to have originated in Spain, and likely reflect Spanish Colonial influence and spread to Latin America ~500 years ago. However, one of the mutations, BRCA1 ex9-12del (a large rearrangement mutation in BRCA1 that is not detectable by conventional sequencing tests) appears to be a Mexican founder mutation, and represents 10-12% of all BRCA1 mutations in Mexican Americans in the U.S. We propose to test a novel economical genomic panel assay (HISPANEL), that has been able to detect nearly 80% of BRCA mutations in U.S. Hispanics for a very low cost (~$25/case), among high risk breast cancer patients in Latin America with a focus in Peru and Colombia. We will also train doctors and nurses there how to provide genetic counseling and genetic testing. Thus, in this international project we will try to make important observations about BRCA mutations among Latin American women, while helping the respective countries create an infrastructure of genetic counseling clinicians, and develop and test low cost genetic testing tools to apply in their home countries. Accomplishing these objectives will enable identification of women at highest risk for breast cancer, so that limited clinical resources can be focused where they are needed the most to detect and detect breast cancer earlier, and to prevent the disease.
Title: Epidemiology and Prevention of Hereditary Breast Cancer in Underserved Hispanics Project description: This project will create and test innovative and low-cost genomic approaches to expand access to personalized medicine among underserved Hispanics in the US and Mexico, using genomic tools that will represent a leap forward for the health care system and have a significant impact on breast cancer prevention. In addition, through this project, collaborating clinicians in the US and Mexico will be trained in Genetic Cancer Risk Assessment (GCRA) by a team of clinicians and researchers at City of Hope who have provided intensive GCRA training to over 400 clinicians from around the world to date. The outcomes of this training will be assessed. Even simple, relatively cost-effective screening measures, such as training in breast self-exam, more frequent breast exams by doctors, and mammographic screening programs targeted to high-risk women are likely to have a significant impact by facilitating diagnosis of smaller, more curable cancers. Identifying women with hereditary breast cancer will enable prevention of new primary cancers, allowing cost-effective allocation of limited healthcare resources for screening and prevention. At least 800 of 1,000 enrolled women will undergo genetic testing, leading to ~120 testing positive for a deleterious BRCA mutation. If they take the recommended actions to reduce risk, there will be 100 fewer breast or ovarian cancers within just the span of the proposed project. This is before considering the amplified impact of genetic knowledge in their families. This will be the largest group of individuals with Mexican ancestry to undergo cancer risk counseling and BRCA gene analyses.
The Division of Clinical Cancer Genetics at the City of Hope has an established research registry and outreach program that includes Olive View-UCLA Medical Center (OVMC) and Los Angeles County + University of Southern California Medical Center. Our program has been providing genetic cancer risk assessment and testing women at high risk for breast and ovarian cancer who are underinsured and Hispanic. Up until now, we have not been able to cover men and women who are at high risk for colon cancer due to a strong family history of the disease. With this new funding, we can add genetic counseling and testing to address this critical gap and provide seed-funding for a pilot program to identify and test hereditary cancer syndrome gene locations in Hispanic and others who are underserved with low income and uninsured status. We have successfully demonstrated ability to efficiently test individuals with high probability of BRCA mutations and now will be able to replicate these methods with the population at high risk for MMR (colorectal cancer causing) mutations.