Research Grants Awarded
Search for Novel Genes Predisposing to Breast Cancer
BACKGROUND. Inherited mutations in BRCA1 and BRCA2 lead to very high risks of breast cancer and account for 10% of breast cancer diagnosed before age 45 and 2% diagnosed at age 45 or later among US women. In addition, inherited mutations in CHEK2 and other genes are associated with more modest, though significantly increased, breast cancer risks. However, most families severely affected with breast cancer have no known deleterious mutations, so their high incidence of breast cancer is unexplained. As-yet-unknown genes, familial clustering of non-genetic risk factors, chance, or a combination of these factors may be responsible. Our goal is to address the first possibility. OBJECTIVE. To identify an additional gene(s) responsible for inherited predisposition to breast cancer in severely affected families. SPECIFIC AIMS. (1) Carry out a genome-wide scan for linkage in highly informative, unexplained breast cancer families. (2) In patients from linked families, fully re-sequence candidate genes. (3) For potentially damaging mutations, compare allele frequencies among unrelated familial breast cancer patients vs controls of two independent series. STUDY DESIGN. AIM 1. The ?discovery series? for the genome-wide scan includes 51 extended families with 312 enrolled breast cancer patients, enriched for younger ages at diagnosis, and their informative relatives. DNA, RNA, and questionnaires are collected for all participants and pathology specimens obtained whenever possible. The genome scan will exploit a very dense map, developed in our lab from 250K SNP and microsatellite markers. Promising regions will be tested by haplotype linkage in 219 additional families, each with 4+ cases of breast cancer. AIM 2. All genes in promising genomic regions will be characterized by bioinformatics tools, then prioritized for sequencing based on expression profile and function, with focus on those interacting with BRCA1/2 or involved in cell cycle control, DNA repair, or steroid metabolism. Candidate genes will be re-sequenced in genomic DNA and cDNA from a patient in each linked family. Each variant will be assessed for co-segregation with breast cancer in the families. AIM 3. Variants will be classified as benign, possibly damaging, or probably damaging using bioinformatics tools. For each gene, the total frequency of all its potentially damaging variants will be compared in 900 familial breast cancer patients and 1500 female ancestry-matched controls. Potentially damaging variants detected in Ashkenazi Jewish (AJ) families will be screened in an independent series of 1600 AJ breast cancer patients (not selected for family history) and 1600 female AJ controls. BENEFITS. For women at inherited high risk of breast cancer, analysis of critical genes enables the development of personalized detection and prevention plans.
Herodotus in ancient Greece, Paul Broca in 19th century France, and Janet Lane-Claypon in early 20th century England all wrote that in some families, women suffered particularly from breast cancer. Throughout this period, physicians could counsel such families but had no way to identify those women very likely to develop breast cancer vs those not. Then very recently, modern tools enabled geneticists to find BRCA1 and BRCA2, and therefore in many families, to distinguish women at extremely high risk from women at the risk of the general population. Success in identifying BRCA1, BRCA2, and other breast cancer-related genes now reveals another challenge: families with many cases of breast cancer but no detectable mutations in any known breast cancer genes. My interest in this problem began during my work as a hospital technician and student in XXXX, where I was responsible for sequencing BRCA1 and BRCA2 in high risk families. I identified inherited mutations in many families, some of which were novel, and including mutations that could not be detected by traditional sequencing. But other families seemed impossible to solve. From the scientific literature, it was clear that other investigators had encountered this problem as well. This year I came to the laboratory of Dr. XXXX in XXXX to work on this question. Dr. XXXX has studied families with breast cancer for almost as long as I?ve been alive. She was responsible for the discovery via mapping of BRCA1. She has collected genealogies, DNA, RNA, and clinical information from thousands of breast cancer patients and their relatives in more than 1300 families. In her lab, I will study 270 families who are very severely affected with breast cancer but have no mutations in BRCA1 or BRCA2. (I am quite convinced of this, because we have used many methods to detect even the most cryptic mutations.) My project will be genome-wide analysis of breast cancer in these families. Complexities include the appearance of both inherited and non-inherited cases in the same family, the possibility that some predisposed women may escape the disease, and the likelihood that different genes will influence risk in different families. With help, I have designed approaches to increase my chances of detecting a gene (or genes) influencing breast cancer risk in spite of these complexities. Identifying genes that explain breast cancer in still unresolved families has both immediate and long-term value. The results will obviously be of use for women in the affected families. In addition, the identification of genes responsible for inherited breast cancer reveals pathways critical to breast cancer development generally. The components of those pathways are natural targets for therapeutic intervention.