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    Research Grants Awarded

    The role of apoptosis gene variants in familial breast cancer

    Study Section:
    Risk, Prevention and Epidemiology

    Scientific Abstract:
    The genetic model that best accounts for the familial aggregation of breast cancer not due to BRCA1 or BRCA2 (BRCA1/2) mutations is a multiplicative, polygenic model. In particular, this model indicates useful discrimination of low- and high-risk groups in the general population based on genetic profiles of the polygenes involved. Identification of such genes, therefore, has the potential to provide significant improvements in intervention and prevention of disease. Apoptosis is an essential defense against hyperproliferation, and loss of function or aberrations of this process are hallmarks of cancer. Hence, genes in the apoptosis pathway have the potential to be part of the genetic profile important for breast cancer risk. Further, given the multiple links between DNA repair and apoptosis, it is possible that apoptosis genes may also act as mediators in breast cancer caused by mutations in BRCA1/2. Thus far, however, the role of genetic variation in the apoptosis pathway has been largely under-studied. The ultimate aim would be to screen as many genes of the pathway as possible; in this study, we have selected six genes (CASP8, CASP10, BIC, BIRC5, FADD and BCL2). These were chosen due to their position in the pathway and their relationship to CASP8, the only apoptosis gene with an established role. In order to thoroughly investigate each gene, we have already selected tagging-SNPs that fully characterize the genetic variation present. Here, we propose to study female breast cancer cases selected from high-risk pedigrees and with strong family histories. Even in a polygenic model, strong family history substantially increases the efficiency of association studies over population-based designs. Our high-risk breast cancer pedigrees were previously used to identify BRCA1/2. However, there remain hundreds of women whose cancer is not explained by BRCA1/2. We will study 941 familial, female breast cancer cases (827 non-BRCA1/2; 114 BRCA1/2) and 941 female, age-matched controls. We will consider multiple outcomes, including breast cancer status, histology, age at diagnosis and survival. Using pedigree-based association and linkage analyses (103 pedigrees) we will identify susceptibility haplotypes. Furthermore, we will perform high-resolution comparative genomic hybridization experiments with an aim to discover functional copy number variants residing on the susceptibility haplotypes identified. Potential future impacts include better diagnosis, management and personalized treatment.

    Lay Abstract:
    It is known that genes play a role in the risk of breast cancer. The identification of two high-risk breast cancer genes (BRCA1 and BRCA2) has made considerable impact on diagnosis and treatment strategies. However, BRCA1/2 genes are rare and only account for a small percentage of all breast cancer cases. The current thinking is that other genes involved in breast cancer risk are common with low risk. However, if an individual has many of these low-risk genes malfunctioning, together they produce a high risk. It has been suggested that the discovery of these common, low-risk genes would provide significant improvements in intervention and prevention. Identifying these genes is, therefore, very valuable. The challenge is to isolate those genes from the total of ~30,000 that exist in humans. A promising route is to study genes based on what is already known about their particular purpose. For example, apoptosis genes transmit signals to cells telling them to die when they stop working properly. Without apoptosis, faulty cells are not managed, and tumors can develop. Apoptosis genes have only just begun to be studied in breast cancer and already show promise of being useful. Recently, a genetic variant in an apoptosis gene called CASP8 was shown to be associated with breast cancer. While the ultimate aim would be to screen all apoptosis genes; in this study we can study only a few and have chosen CASP8 and 5 others known to interact with it (CASP10, BID, BIRC5, FADD, and BCL2). We will thoroughly study multiple genetic variants in each gene in a case-control design. Women in the study include some with mutations in BRCA1/2 (114), but the majority do not have such mutations (827 women). A unique feature of our study is the 941 cases occur in high-risk families, a powerful design for detecting associated genetic variants, that will also allow us to look at how genetic variants inherit in the families. We will perform analyses for breast cancer status, age at diagnosis, severity and survival. We will also look for interactions across genes. Lastly, we will use new experiments designed to locate deletions and insertions to identify possible underlying causal variants. Understanding the role of apoptosis genes in breast cancer will help us understand susceptibility and characteristics of, and survival from, the disease.