American Cancer Society Professor Departments of Medicine and Genome Sciences University of Washington, Seattle, WA
Project 1: Co-Investigators: Moien Kanaan, PhD, Bethlehem University, Palestinian Authority 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.
Project 2: The New York Breast Cancer Study Co-Investigator: Joan H. Marks, MS, New York Breast Cancer Study at Sarah Lawrence College, Bronxville, NY
The goal of the New York Breast Cancer Study (NYBCS) 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, these researchers use genomic sequencing to evaluate DNA from women who have developed breast cancer and from their relatives. In 2012-2013, they studied DNA from NYBCS participants who had no mutations in BRCA1 or BRCA2 but whose families were nonetheless severely affected with breast cancer.
Dr. King's team discovered that breast cancer in approximately one-fifth (21%) of these families could be explained by inherited mutations in other genes. This discovery suggests that in future, clinical testing for inherited predisposition to breast cancer should include other genes in addition to BRCA1 and BRCA2.
But what next? While it is obviously important and useful to learn the causes of breast cancer in a fifth of unresolved families, this group hopes to solve them all. The next step of the NYBCS will be to search, genome-wide, for mutations in regulatory regions that may influence proper timing and expression of critical genes.
Project 1: 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.
Project 2: The goal of the New York Breast Cancer Study 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, Drs. King and Marks use genomic sequencing to evaluate DNA from women who have developed breast cancer and from their relatives. In fall 2013, they began a major genome-wide sequencing effort to identify mutations in regulatory regions that may influence timing and expression of genes critical to breast cancer. Thus far with this approach, the researchers have identified one class of mutation not previously detected in a breast cancer gene: mutation of a single DNA nucleotide deep inside a non-coding genomic region (an intron) that leads to appearance of a new coding region (an exon) in the wrong place. The new “impostor” coding region does not retain the reading frame of the normal gene, so introduces a premature truncation of the protein. The researchers expect multiple different, heretofore under-appreciated classes of mutations to be revealed by whole genome sequencing. Their hypothesis is that for mutation generally, and for mutations predisposing to breast cancer in particular, everything that can go wrong, will. They anticipate that each one of these events will be individually very rare, but that collectively they may not be rare. 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 indicates that they likely have inherited predisposition to breast cancer, but who have normal sequences of all known breast cancer genes.
Mary-Claire King is American Cancer Society Research Professor of Genetics and Medicine at the University of Washington. Work in her lab focuses on genetic analysis of breast and ovarian cancer. Dr. King was the first to prove that breast cancer is inherited in some families. She is now studying BRCA1 and BRCA2 and searching for other breast and ovarian cancer genes. Her other medical research interests include genetic analysis of inherited deafness and systemic lupus erythematosus. Her lab is also interested in human genetic diversity and evolution, and in the application of DNA sequencing to human rights problems.
Dr. King received her BA in Mathematics from Carleton College, her PhD in Genetics from University of California at Berkeley, and her postdoctoral training at UC San Francisco. She has served on the National Commission on Breast Cancer of the President's Cancer Panel, the advisory board of the National Institutes of Health (NIH) Office of Research on Women's Health, the Council of the NIH Fogarty Center, the advisory board of the National Action Plan for Breast Cancer, the NIH Breast Cancer Program Review Group, the Board of Scientific Counselors of National Cancer Institute, the Board of Scientific Counselors of Memorial Sloan-Kettering Cancer Center, the National Research Council committee to advise the Department of Defense on their Breast Cancer Research Program, and many NIH study sections. Abroad, she has served as Consultant to the Commission on the Disappearance of Persons of the Republic of Argentina and has carried out DNA identifications for the United Nations War Crimes Tribunal.
Dr. King has been elected to Phi Beta Kappa and Sigma Xi, as a Fellow of the AAAS, to the Institute of Medicine (and its Council), to the American Academy of Arts and Sciences,and as honorary chair for Washington state for the 50th Anniversary of the United Nations. She has received the Clowes Award for Basic Research from the American Association for Cancer Research, the Jill Rose Award from The Breast Cancer Research Foundation, the Brinker Award from the Komen Foundation, a Woman of the Year Award from Glamour magazine, and honorary doctorates from Carleton, Smith, Bard, and Dartmouth Colleges. In 2012, Dr. King was elected as President of the American Society of Human Genetics and elected to the American Philosophical Society.
Dr. King has one daughter, Emily, who lives and works in Berkeley.