Research Grants Awarded
Admixture Mapping For Breast Cancer Susceptibility Genes Among African American Women
Investigator Initiated Research
Background and Rationale: Breast cancer incidence and mortality vary among different racial and ethnic groups. Although the incidence of breast cancer among African American women is lower than the incidence among Caucasian women, African American women have a higher mortality from breast cancer than Caucasian women. African American women are diagnosed more frequently with tumors which are higher grade and negative for estrogen receptor (ER) expression. Although environmental, reproductive and socioeconomic differences may play a role in explaining these differences, genetic factors may also contribute. Studies that have adjusted for known environmental, reproductive and socioeconomic risk factors and for frequency of screening, have consistently found that the higher proportion of ER-negative and higher grade tumors among African American women is not explained by these risk factors.
African Americans are known to be a genetically admixed population, with ancestry from African, European and Native American populations. Admixed populations such as African Americans provide a unique opportunity for efficient mapping of susceptibility genes by an approach called ?admixture mapping.? Admixture mapping utilizes the enhanced linkage disequilibrium (association between markers on the same chromosome) in admixed populations to efficiently map genes. Our group has recently used this approach in African Americans to identify a locus that controls the level of interleukin 6 levels and another locus that controls circulating white blood cells among African Americans.
Hypothesis: We hypothesize that among African Americans, different subtypes of breast cancer are due to genetic variants (alleles) from different ancestral populations. More specifically, we hypothesize that certain alleles which predispose to certain types of tumors (ER-negative, high grade) may be more common in African ancestral populations. Conversely, other alleles which may predispose to other types of tumors (ER-positive, low grade) may be more common among European populations. Furthermore, we also hypothesize that these genes may be identifiable by admixture mapping in African Americans, a population of mixed African and European ancestry.
(1) We will perform whole genome admixture mapping to identify genomic loci (regions of the genome) which underlie differences in breast tumor subtypes among African Americans. Specifically, we will genotype ~1500 markers that are informative for ancestry (ie have high allele frequency differences between Europeans and West Africans) and are evenly spaced throughout the genome. We will then use these markers to search the genome for loci that are associated with breast cancer overall and with subtypes of breast cancer (ie ER-postive and ER-negative)
(2) We will fine map the genomic loci identified in specific aim 1 to discover the genes and specific genetic variants that underlie the differences in breast tumor subtypes for breast cancer. Specifically, we will genotype polymorphisms within the loci identified by admixture mapping to identify the causative genetic variant/s responsible for the peaks identified by specific aim 1. Genotyping will include dense coverage with several hundred single nucleotide polymorphisms within the loci, to saturate the regions. Ultimately we anticipate identifying one or more genetic variants that underlie breast cancer susceptibility among African American women.
We will utilize samples and data from three studies: an existing case-control study of in the San Francisco Bay Area, a funded, ongoing case-control study in the New York/New Jersey Area and a funded, ongoing case-only study from the Cancer Family Registry (an NCI funded study of women with breast cancer and strong family history).
Impact: Our project will help to understand the higher risk of ER-negative, PR-negative breast cancer among African American women. If we are successful in identifying a genetic locus and ultimately a genetic variant/s that account for this type of disease, we may be able to develop a test based on this variant/s. By testing for this genetic variant/s, clinicians may be able to identify high risk women before diagnosis and offer them intensive screening. Using this approach, high risk women will be diagnosed at an earlier stage in more women which will reduce the morbidity and mortality that comes from late stage diagnosis.
Breast cancer among African American women often presents with different characteristics compared with breast cancer diagnosed among Caucasian women. Compared to Caucasian women, African American women are more frequently diagnosed with tumors that do not express the estrogen receptor. This results in a clinically important difference in treatment, since estrogen receptor negative tumors cannot be treated with drugs that target the estrogen receptor such as Tamoxifen or aromatase inhibitors. Therefore, women with estrogen receptor negative breast cancer have fewer treatment options. In addition, although the rate of breast cancer over a lifetime is higher among Caucasian women, the rate of breast cancer among women 35 and under is higher in African American women. Although some of these factors may be due to environmental and socioeconomic factors, genetics may play a role as well.
We hypothesize that the increased incidence of estrogen receptor negative tumors may be, at least partially, due to different genetic risk factors among African American women. Our proposal will search for genes that contribute to breast cancer risk among African American women.
African Americans are of mixed ancestry with both African and European ancestry. We will use the knowledge of mixed ancestry in African American women to enhance our ability to search for genes. Using genetic markers that are known to be either more common in West Africa or in Europe, we can search for genetic regions where the African American breast cancer patients share ancestry. For example, African American women with estrogen receptor breast cancer may share ancestry at the same region of the genome that predisposed them to that type of breast cancer.
This approach called ?admixture mapping? has recently been used to identify genes for prostate cancer. We propose to use this approach to investigate breast cancer risk in African American women. Specifically, we will use this approach to search for genes that increase ER-negative breast cancer risk among African American women. This approach will provide us with a general location of a potential gene or genes that contribute to the type of breast cancer that is estrogen receptor negative among African American women.
Once we find the general location by searching for regions of shared ancestry among the cases, we will examine those regions in more detail by typing additional genetic markers. As we type additional genetic markers, we will be able to narrow down the region and eventually identify the causative gene or genes.
Identifying a gene or genes that increase the risk in African American women for estrogen receptor negative breast cancer may be important for several reasons. First, it may help us to identify women at particularly high risk of breast cancer in this population to target them for early, intensive screening. For example, younger women could be tested for this gene and, if they are found to be positive, they could be enrolled in programs that target them for very early and intensive screening. As a result, they may be diagnosed at an earlier stage and therefore have greater chance of cure from their cancer.
Second, by understanding which gene underlies this type of cancer, we may be able to gain additional insights into what causes this type of breast cancer. This may help other scientists looking for new treatments for this type of breast cancer.