Shaare Zedek world leaders in fighting Breast Cancer Ephrat Levy-Lahad, MD Director, Medical Genetics Institute Shaare Zedek Medical Centre, Jerusalem, Israel Current Research Dr. Levy-Lahad is working on two related projects, the Israel Breast Cancer Study and Middle East Breast Cancer Study, with BCRF colleagues, Mary-Claire King and Moien Kanaan. Results from the Israel Breast Cancer Study (IBCS) led by Dr. Levy-Lahad and colleagues previously showed that breast and ovarian cancer risks are high in women who carry mutations in BRCA1 or BRCA2, even if these women did not have a family history of cancer. Such women would not be referred for testing until they become the first in their family to be affected. In their previous study, Dr. Levy-Lahad and colleagues explored the option of population-based genetic screening in Ashkenazi Jews, because in this ethnic group, three common mutations are present that facilitate testing in large numbers of individuals. With modern sequencing tools, population-based screening could be applicable to women of all ancestries. However, whereas one in 40 Ashkenazi Jews is a BRCA1 or BRCA2 mutation carrier, the frequency of BRCA mutation in other populations is not known. The research team is working to determine the frequency of BRCA1 and BRCA2 mutations in both affected and unaffected women in a heterogeneous population. This will be performed using non-Ashkenazi Jews as a model for other diverse populations, like those of the USA or Europe. Mutation frequency is likely to be lower than for Ashkenazi Jews, but may be high enough to justify population screening for inherited predisposition, confirming a new paradigm for cancer prevention. These studies will facilitate the application of genetic testing for BRCA1 and BRCA2 to advance precision medicine. Genetic analysis and medical follow-up services for breast and ovarian cancer risk among Israeli women in the Middle East are highly developed. Comparable services for other women in the region were not available, however, until the initiation of the Middle East Breast Cancer Study (MEBCS) in 2007 with support from BCRF. The goal of MEBCS is to provide genetic counseling, analysis and follow-up services to underserved women in the region, particularly Palestinian women. The MEBCS is directed jointly by Dr. Levy-Lahad, Moien Kanaan, PhD and Mary-Claire King and is a sister project of the New York Breast Cancer Study (NYBCS), directed by Dr. King, and the IBCS, also sponsored by BCRF. The MEBCS has enrolled 1000 breast cancer patients of Palestinian and Arab-Israeli origins and has completed genomic analysis comprising BRCA1 and BRCA2 and more than 30 other known and candidate breast cancer genes for 400 of these patients. In 12 percent of the young-onset and familial patients, they have identified the inherited mutation responsible for their disease. These mutations appeared not only in BRCA1 and BRCA2 but in a total of 11 different breast cancer genes. The observation supports the hypothesis that breast cancer has many different genetic causes and that therefore, studying this population will enable discovery of new genes underlying breast cancer in women from all parts of the world. In the coming year, the team will study severely affected families in which no mutations were identified. In particular, they will ask whether any recessive mutations (i.e., inherited from both sides of the family) may be responsible for their breast cancer. In parallel, the researchers are establishing a comprehensive infrastructure for breast and ovarian cancer genetics services on the West Bank with clinical, laboratory, and bioinformatics capacities. They are providing genetic counseling and testing for breast and ovarian cancer patients at Augusta Victoria Hospital in East Jerusalem and at El Hussein Hospital in Beit Jala, a major breast cancer referral center on the West Bank. Next year, they will expand these services to the Istishari Hospital and the Dunya Cancer Center in Ramallah. In addition, genomic sequencing is now established in Dr. Kanaan’s laboratory in Bethlehem.