American Cancer Society Professor Departments of Medicine and Genome Sciences University of Washington, Seattle, WA
Dr. King is working with several BCRF colleagues on two studies that are focused on understanding the genetic susceptibility of breast cancer. The goal of the New York Breast Cancer Study conducted with Ms. Joan Marks is to identify all genes responsible for inherited predisposition to breast cancer among women of Ashkenazi Jewish ancestry and by extension among women of all ancestries. To discover these genes, Dr. King and Ms. Marks use genomic sequencing to evaluate DNA from women who have developed breast cancer and from their relatives to identify inherited mutations in genes critical to the development of breast cancer. BRCA1 was originally identified by this approach, and sister genes of BRCA1 have been identified by this approach as well.
With the development of relatively low cost whole genome technologies, the research team has identified new classes of mutations in BRCA1 and BRCA2 and other known breast cancer genes. Examples of these include mutations of single DNA nucleotides that affect normal protein synthesis and chimeric genes which, as the name suggests, are mutations with the head of one gene and the tail of another. These mutant genes cannot create normal products and lead to breast cancer.
The team expects that their methods will continue to reveal multiple different, heretofore under-appreciated classes of mutations. They predict that each one of these mutations will be individually very rare, but collectively more common.
The practical importance of this phase of the NYBCS will be to reveal the range of mutations that can occur among women with breast cancer whose family history suggests inherited predisposition to breast cancer, but also for whom the critical mutations have not yet been found.
The Middle East Breast Cancer Study (MEBCS) is directed jointly by Ephrat Levy-Lahad, MD, of Shaare Zedek Hospital and Hebrew University, Jerusalem, Israel; Moien Kanaan, PhD, of Bethlehem University, Bethlehem, Palestinian Authority, and Dr King. The MEBCS is a sister project of the New York Breast Cancer Study (NYBCS), directed by Dr King, and the Israel Breast Cancer Study (IBCS), directed by Dr. Levy-Lahad, which are also sponsored by BCRF.
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 in 2007 with support from BCRF. BCRF has been a continuous sponsor of the MEBC, the goal of which is to provide genetic counseling, analysis and follow-up services to women of all ancestries in the region.
As of this year, the MEBCS has enrolled 852 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 344 of these patients. The investigators will continue to screen all breast cancer genes in this group of patients in order to determine the frequency of mutations of each gene and how each mutation affects the function of its gene. This year they will also extend their outreach to additional Palestinian patients through a new collaboration with the El-Hussein Hospital in Beit Jala (between Bethlehem and Jerusalem).
A striking observation of the study to date is that many patients from families very severely affected with breast cancer have no damaging mutation in any of the known breast cancer genes. The observation supports the hypothesis that breast cancer has many different genetic causes and therefore that studying this population will enable discovery of new genes underlying breast cancer in women from all parts of the world.
Mary-Claire King, PhD, is American Cancer Society Professor at the University of Washington, Seattle. She was the first to show that breast cancer is inherited in some families, as the result of mutations in the gene that she named BRCA1. In addition to inherited breast and ovarian cancer, her research interests include the genetic bases of schizophrenia, genetic disorders in children, and human evolution. She pioneered the use of DNA sequencing for human rights investigations. Dr. King has been elected to the National Academy of Sciences, the American Academy of Arts and Sciences, the Institute of Medicine, the American Philosophical Society, and as a foreign member of the French Academy of Sciences. She has served on the Advisory Committee to the Director of NIH; the National Commission on Breast Cancer of the President’s Cancer Panel, multiple councils and study sections of the NIH, and as past president of the American Society of Human Genetics.