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    Research Grants Awarded

    Genetic Risk Factors For Brca1 Deficient And Basal Breast Cancer

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    Individuals with germline mutations in the BRCA1 tumor suppressor gene have a substantially increased risk of developing breast and ovarian cancers as compared to the general population. The cumulative risk of breast cancer by age 70 for BRCA1 mutation carriers is estimated at 65%. While these risk estimates show that women carrying deleterious BRCA1 mutations are at extremely high risk for developing breast cancer they also indicate that not all carriers will become affected. In addition to incomplete penetrance, there is also considerable variability in the age of diagnosis of breast cancer among the carriers who develop breast cancer. Even though the variable penetrance among BRCA1 mutation carriers is well defined, to date no method has been developed that clearly distinguishes between BRCA1 mutation carriers at high-risk and those at lower-risk. Our inability to distinguish between these carriers is a significant clinical issue. Specifically, because all women diagnosed with BRCA1 mutations are counseled using the same elevated risk estimates for cancer, prophylactic oophorectomy and mastectomy are often recommended as risk reduction strategies for the mutation carriers who will never develop breast cancer in their lifetime or who may not develop breast cancer until late in life. If BRCA1 mutation carriers at lower risk can be identified it may be possible for some of these carriers to avoid prophylactic surgery and to adopt instead a screening strategy for cancer prevention, or to delay prophylactic surgery until after childbearing. In contrast, carriers found to be at higher risk might benefit from earlier direct intervention, additional screening modalities and chemoprevention. Our goal in this study is to identify previously undefined genetic risk factors involved in the modification of cancer risk in BRCA1 carriers with the intent of developing risk models to identify BRCA1 carriers at increased and decreased risk of breast cancer. We have recently completed a GWAS of sporadic breast cancer that resulted in the identification of five single nucleotide polymorphisms (SNPs) that are associated with an increased risk of breast cancer. Based on the success of this approach, we propose to identify genetic modifiers of breast cancer risk in BRCA1 carriers through a GWAS of samples from BRCA1 mutation carriers collected through an international consortium. We will rigorously evaluate common variants through a multi-stage approach and select the most significantly associated with breast cancer risk as candidate genetic modifiers. The specific aims are: Aim 1: To conduct a genome-wide association scan to identify risk factors associated with breast cancer risk in BRCA1 mutation carriers. We will genotype 2,000 BRCA1 carriers with young onset breast cancer and 2,000 older unaffected BRCA1 carriers on Infinium 550 arrays that include 550,000 SNPs using a pooling strategy. SNPs will be ranked by statistical significance of association with risk of breast cancer. This approach results in 80-fold cost savings over a standard GWAS. Aim 2: To replicate the associations between candidate genetic risk factors and breast cancer. The 7600 SNPs displaying the most significant associations with breast cancer risk in Aim #1 will be genotyped in 2,000 BRCA1 carriers affected by breast cancer and 2,000 unaffected BRCA1 carriers using custom Infinium Arrays. Genotype data from Stages 1 and 2 will be combined to increase statistical power and the 384 SNPs displaying the most significant association with breast cancer risk will be selected for further characterization. Aim 3: To validate the associations between candidate genetic risk factors and breast cancer risk in BRCA1 mutation carriers. The original 2,000 affected and 2,000 unaffected BRCA1 carriers from Aim #1 will be genotyped for the 384 SNPs most significantly associated with breast cancer risk in Aim 2 using an Illumina Goldengate assay. These samples will be re-genotyped for the most significant SNPs because the pooling strategy in Aim #1 does not provide individual genotypes for calculation of effects on risk. Genotype data from Stage 3 will be combined with data from Stage 2 and the SNPs will again be ranked by significance of association with breast cancer risk. At the conclusion of this study we expect to have validated a number of SNPs from various regions in the genome that alter the age of onset/risk of breast cancer in BRCA1 carriers. These SNPs may prove useful at the clinical level through identification of BRCA1 carriers at lower risk of breast cancer who can delay or avoid prophylactic mastectomy or oophorectomy and identification of carriers at very high risk who may benefit from prophylaxis at a younger age. Similarly, because BRCA1 associated breast tumors are predominantly of the aggressive basal (ER-ve, PR ?ve, Her2 ?ve, CK5/6 +ve) type the SNPs identified through this study may prove useful in the identification of women at risk of this type of cancer. The results will also be useful for additional studies of the interactions of these factors with other genetic and environmental risk factors as well as functional studies aimed at understanding the influence of these SNPs on gene expression and/or function. In this way the study is also expected to improve our understanding of the etiology of breast cancer.

    Lay Abstract:
    Mutations in the BRCA1 gene are thought to confer a high risk (65%) of developing breast cancer by age 70 on carriers. However, studies have shown that there is substantial variation in the age of onset and the site of cancer among BRCA1 mutation carriers. In fact, we now know that about 35% of all BRCA1 mutation carriers will never develop breast cancer. Unfortunately, it is not currently possible to identify mutation carriers who will develop cancer in their lifetime and those who will not. If this was possible then many mutation carriers at comparatively low-risk of breast cancer could delay or even avoid debilitating prophylactic mastectomy and oophorectomy that is currently used to reduce risk of breast and ovarian cancer. In addition, the mutation carriers at comparatively elevated risk could opt for earlier intervention to prevent breast and/or ovarian cancer. The absence of breast cancer in 35% of BRCA1 mutation carriers is strong evidence for the existence of genetic mutations that have subtle effects on genes and are common in the general population. Each so-called modifier of risk probably confers only a small to moderate increase in the lifetime breast cancer risk. However, when several modifiers are inherited together and when modifiers are inherited in combination with a more significant BRCA1 mutation, the modifiers may determine if and when a carrier developed breast cancer. As part of a large consortium we have recently identified several of these risk modifiers that influence the risk of sporadic breast cancer in the general population and also influence the risk of breast cancer in BRCA2 mutation carriers, but not in BRCA1 mutation carriers. This is strong evidence that these modifiers exist and are important regulators of cancer. However the results also indicate that the risk modifiers in sporadic breast cancer are different from the modifiers associated with BRCA1 mutation carriers. This is not unexpected given the recent finding that nearly all BRCA1 mutation carriers develop aggressive basal tumors (estrogen receptor negative, progesterone receptor negative, and Her2 negative) that account for only 15% of all sporadic breast tumors. Here we propose to undertake a genome wide association study for BRCA1 carriers to identify genetic risk modifiers for these individuals. This involves testing 4,000 BRCA1 carriers for the presence of 550,000 polymorphisms spread throughout the human genome to determine which polymorphisms correlate with altered risk of breast cancer. These 4,000 carriers have been collected as through an International Consortium of 45 groups that are working with the principal investigator of this proposal. We will take the innovative approach of pooling these samples in order to reduce costs for the first Stage of the study by 80-fold. We will then attempt to replicate our findings in another set of 4,000 BRCA1 carriers from the consortium. The specific aims of the study are: Aim 1: To conduct a genome-wide association scan to identify risk factors associated with breast cancer risk in BRCA1 mutation carriers. We will genotype 2,000 BRCA1 carriers with young onset breast cancer and 2,000 older unaffected BRCA1 carriers on Infinium 550 arrays that include 550,000 polymorphisms using a pooling strategy. Polymorphisms will be ranked by statistical significance of association with risk of breast cancer. Aim 2: To replicate the associations between candidate genetic risk factors and breast cancer. The 7600 polymorphisms displaying the most significant associations with breast cancer risk in Aim #1 will be genotyped in 2,000 BRCA1 carriers affected by breast cancer and 2,000 unaffected BRCA1 carriers using custom Infinium Arrays. The 384 polymorphisms displaying the most significant association with breast cancer risk will be selected for further characterization. Aim 3: To validate the associations between candidate genetic risk factors and breast cancer risk in BRCA1 mutation carriers. The original 2,000 affected and 2,000 unaffected BRCA1 carriers from Aim #1 will be re-genotyped for the 384 polymorphisms most significantly associated with breast cancer risk in Aim 2. Genotype data from Stage 3 will be combined with data from Stage 2 and the polymorphisms will again be ranked by significance of association with breast cancer risk. At the conclusion of the study we expect to have identified a number of polymorphisms that influence breast cancer risk and perhaps age of onset of breast cancer in BRCA1 carriers. These polymorphisms may prove useful at the clinical level through identification of BRCA1 carriers at lower risk of breast cancer who can delay or avoid prophylactic mastectomy or oophorectomy and identification of carriers at very high risk who may benefit from prophylaxis at a younger age. In work that goes beyond this proposal these polymorphisms will have to be integrated into a risk prediction model before they can be used for clinical purposes. Similarly, because BRCA1 associated breast tumors are predominantly of the aggressive triple-negative basal type the polymorphisms identified through this study may prove useful in the identification of women at risk of this type of cancer. The results will also be useful for additional studies of the interactions of these factors with other genetic and environmental risk factors as well as functional studies aimed at understanding the influence of these SNPs on gene expression and/or function. In this way the study is also expected to improve our understanding of the etiology of breast cancer.