Professor, Molecular Genetics
Dean of Science and Director
Hereditary Research Laboratory
Co-Investigators: Mary-Claire King, PhD, University of Washington, Seattle, WA and Ephrat Levy-Lahad, MD, Shaare Zedek Medical Center, Jerusalem, Israel
The general aim of this project is to determine the genetic basis of inherited predisposition to breast cancer in the Palestinian Arab population, within the context of establishing the necessary infrastructure to provide cancer genetics services. While the incidence of breast cancer in Arab women is approximately one third that of Israeli Jews, it occurs more often in younger women, has poorer prognostic characteristics, and often clusters within extended families. This suggests that an inherited component is likely in many cases. In addition to the clinical implications of this project to these underserved women and their families, because this population has not been studied extensively, the researchers have already identified novel mutations in known genes, and expect to determine new inherited cancer genes which will be relevant to women of all ancestries world-wide.
This international research team originally aimed to assess the mutational spectrum, prevalence, and risk associated with BRCA1 and BRCA2 mutations among Palestinian and Arab-Israeli women. With the emergence of new sequencing technologies, they have expanded this goal to a global genomic analysis of the genetics of breast cancer in this population, including BRCA1 and BRCA2, as well as assessing the contribution of additional genes as they become known and aiming to identify novel breast cancer genes.
The researchers have enrolled over 1,700 Ashkenazi Jewish individuals (80% women) in a screening program for the three BRCA1 and BRCA2 mutations common in this population. They identified 32 carriers of BRCA1 or BRCA2 mutations. Forty percent of these carriers did not have significant family history, and would not have been identified without a universal screening program. Only one-third of the carriers' first degree relatives have been tested so far. Although and another 17 carriers were identified among relatives of carriers, this low rate of relatives' referral underscores the fact that general screening may circumvent familial barriers to sharing genetic information among relatives.
About 60% of people offered testing decided to participate. Women were more interested in being tested than men, and younger women (<70 yrs) more than older women. Having children or daughters did not affect participation in screening, suggesting that women have genetic testing to promote their own health. To facilitate large-scale screening, participants were only given written material before being tested, rather than receiving full genetic counseling with a genetic counselor. At one week post testing and 6 months after receiving test results, over 90% of people were highly satisfied with having participated. Knowledge score was 7/10 at both time points, and only 1-2% reported stress related to testing. These results suggest that universal, large scale genetic screening to prevent breast and ovarian cancer is feasible without significantly compromising satisfaction, knowledge and test-related stress. However, the investigators will also compare this directly to traditional genetic counseling.
In the Middle East, genetic analysis and medical follow-up services for breast and ovarian cancer risk among Jewish women are among the best in the world. But comparable services were not available women of other ancestries in the region. In 2007, BCRF sponsored the creation of the Middle East Breast Cancer Study (MEBCS), the goal of which is to provide genetic analysis and genetic counseling follow-up services, of the same excellent standard, to women of other ancestries in the region, and has sponsored the MEBCS continuously ever since. 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 Mary-Claire King, PhD, of the University of Washington, Seattle, USA. 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, both of which are also sponsored by BCRF.
As of this year, the MEBCS has enrolled 799 breast cancer patients of Palestinian and Arab-Israeli origins. Thus far the researchers have carried out genomic analysis for 268 of these patients: 147 patients with family history of breast or ovarian cancer, in addition to their own breast cancer, and 121 patients diagnosed with invasive breast cancer at or before age 40. Genomic analysis of DNA of these patients, as for NYBCS and IBCS patients, comprises sequencing BRCA1 and BRCA2 and more than 30 other known and candidate breast cancer genes. Sequencing is performed using BROCA, the multi-gene targeting and next-generation sequencing approach developed, validated, published, and operationalized in the clinical setting by Dr. King’s lab.
Of the familial and young-onset breast cancer patients, 12% had inherited a damaging mutation in BRCA1, BRCA2, or one of the other breast cancer genes. Eleven different genes carried mutations in patients from this population. Among breast cancer patients with family history of breast or ovarian cancer, 16% carried a damaging mutation in a breast cancer gene; among young-onset breast cancer patients, 7% carried such a mutation. About half of the mutations were in BRCA1 or BRCA2 and about half of the mutations were in other genes involved in repair of damaged DNA. The researchers are now screening these mutations in the total cohort of >800 patients in order to determine the frequency of each. They are also studying how each mutation affects the function of its gene. In the next months, they will also extend BROCA analysis to 70 additional patients from the MEBCS, 44 with familial breast cancer and 26 with young-onset breast cancer.
A striking observation of the study this year is how many patients from very severely affected MEBCS families have no clearly damaging mutation in any of the known breast cancer genes. The researchers speculate that breast cancer in these families is due either to mutations in as-yet-unidentified regulatory regions of known breast cancer genes that are far from the genes themselves (i.e. a long distance genomic trouble-maker effect), or to an as-yet-unknown gene. The observation fits ytheir hypothesis that breast cancer in the Palestinian population 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.
Dr. Moien Kanaan is a leading Palestinian geneticist. Over the last 15 years Dr. Kanaan has been investigating the genetically isolated Palestinian population and its high consanguinity rate in identifying genetically based disease gene. This includes hearing loss, skin abnormalities, and congenital heart diseases. Utilizing large consanguineous Palestinian kindreds, Dr. Kanaan's collaborative work has been able to profile novel and variant alleles undermining hearing loss and Epidermolysis Bullosa in Palestinian population and just recently mapped and identified new hearing loss causing genes.
Currently Dr. Kanaan is Professor and Dean of Science, and the Director of the Hereditary Research Lab at Bethlehem University. Dr. Kanaan has been a member of Research Task Force in Palestine and has participated in many international research effort and scientific networks. Dr. Kanaan is a recipient of many research and scientific awards and is a pioneer in initiating the "Palestinian center of disease control."