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"Genetic Modifiers of BRCA Penetrance"
RISK and Prevention, Epidemiology
Background : Genetic testing provides new opportunities for the prevention of hereditary cancers in the 0.5-1 million individuals in the U.S. carrying mutations of the BRCA1 and BRCA2 tumor suppressor genes. The cancer risk (penetrance) associated with these mutations, however, remains a point of controversy. These differences strongly suggest a role for other as-yet unidentified genetic factors. Single nucleotide polymorphisms (SNPs) identified by the Human Genome Project can now be utilized in a genomic search for modifiers of BRCA1/2 . By performing a genomic scan in a genetic isolate (Ashkenazim), linkage disequilibrium (LD) can assist in novel gene identification. Objectives/Hypothesis: The central hypothesis of this proposal is that the predisposition to breast cancer conferred by a germline mutation in BRCA1 or BRCA2 is subject to modulation by genetic cofactors . The Specific Aims of the study are to: 1) Perform high density genomic scans in carriers of a specific BRCA founder mutations who have been a) affected by breast cancer at an early age (< 40) and b) who have not been affected by breast cancer after age 65. 2) Utilize LD mapping to further identify putative modifier loci revealed by the genomic scan, including use of high resolution SNP panels and mutational analysis of candidate genes. 3) To analyze if candidate modifier genes impact age at onset in BRCA and non- BRCA associated breast cancer. Study Design : We will first utilize the Affymetrix 500K SNP chip to perform genomic scans in Ashkenazi carriers of the BRCA founder mutations who have had breast cancer before age 40 and in healthy elderly mutation carriers unaffected by breast cancer after age 65. Significant loci identified by whole-genome scan will be further explored by use of fine resolution SNP panels and/or mutational analysis of candidate genes. Candidate modifier genes (or tagged SNPs) will be investigated as modifiers of age-at-onset in a large case series of > 1,000 BRCA and non- BRCA associated breast cancer. Relevance : Molecular characterization of genes that modify BRCA penetrance will provide insight into genetic pathogenesis of both hereditary and non-hereditary breast cancers in which BRCA underexpression may be somatically acquired. The demonstration that cancer risk in BRCA heterozygotes may be modified by polymorphisms in other genes will be of immediate importance in the risk stratification and preventive care of these women and their families.
Background : From 0.5 to 1 million women and men in the U.S. carry alterations of the BRCA1 and BRCA2 genes. In women with these mutations, choices for cancer detection and prevention range from increased screening (e.g. by mammography, MRI) to the most extreme intervention: preventive surgery. Unfortunately, some women in families with a BRCA mutation may face a 90% risk of cancer, whereas other families inheriting the same mutation may have less than half this risk. Diet or hormone exposures seem to account for a small part of this difference in risk, but it appears that other, as-yet unknown, genetic factors may also be important. Until these other genetic risk factors are identified, it will not be possible for individuals to make the most informed decision regarding their preventive care. Perhaps most significantly, factors that modify risk in women with BRCA mutations may also be relevant to risks faced by the larger number of women who do not carry BRCA mutations. In this proposal we will focus on individuals of Eastern European (Ashkenazi) Jewish ancestry as an example of a “genetically isolated” population. In these populations, the ability to find markers linked to cancer causing genes is much higher. However the findings from this group should be relevant to all populations of the world. Methods: We will compare the genomes of patients with a particular common BRCA mutation who a) have breast cancer at very young age and b) who have never had breast even at late age. In this way we will discover genetic factors that are both “protective” against breast cancer, and, conversely, genetic factor which increase breast cancer risk. We will use the highest possible density of genomic scan, and will then follow this with additional studies to map the regions identified. We will then test if these new genetic markers of risk are associated with early versus late age of onset in breast cancer patients with and without BRCA mutations. Significance : By mapping new genes, and understanding the interactions of known genes, we will achieve greater insight into the genetic pathways that cause hereditary as well as non-hereditary breast cancer. The demonstration that cancer risk in women carrying alterations in the BRCA genes may be modified by other genes will be of immediate importance in the preventive care of such women, and will have a significant impact on the overall goal of breast cancer prevention and control.