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Mary-Claire King, PhD
American Cancer Society Professor
Departments of Medicine and Genome Sciences
University of Washington
Goal: To characterize the genetic susceptibility to breast cancer in high-risk groups and improve screening and risk stratification strategies.
Impact: Mutations in the BRCA genes, BRCA1 and BRCA2, are the most potent inherited risk factors for breast and other cancers. While technologies to detect mutations in the BRCA and other cancer risk genes have been successful in determining the causal factor in many familial breast cancers, they are limited in their ability to detect certain gene alterations which can also result in heightened risk of breast cancer. Dr. King is leading efforts to uncover previously undetectable modifications to BRCA and other genes in participants of the New York Breast Cancer Study.
What’s next: This year, her team will use their newly developed approach to reveal familial DNA mutations that were not detectable by any previous technology.
Women who have inherited mutations in the BRCA1 or BCRA2 genes have a significantly higher risk of getting breast or ovarian cancer, and these mutations are much more common in Jewish families of Eastern European (Ashkenazi) descent. However, there are other genes and other mutations that cause breast cancer in this population, some of which cannot be detected by current methods. Dr. King is using new technologies that will allow for the identification of additional underlying genetic causes of breast cancer in this high-risk group.
Full Research Summary
Research area: Understanding the inherited susceptibility of breast cancer in women of Ashkenazi Jewish heritage.
Impact: Mutations in the BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer. Jewish people of Ashkenazi descent are far more likely to carry these mutations than the rest of the population; however, there are other mutations that predispose this group to breast cancer. Dr. King is integrating genomic technologies that will reveal these mutations, which have not been detectable by other methods. Her efforts may lead to improvements in screening guidelines for families severely affected by inherited risk, so that all who are at risk of breast cancer can be identified before the disease develops.
Current investigation: The goal of the New York Breast Cancer Study (NYBCS), led by Dr. King, is to identify and characterize genes responsible for inherited breast cancer among women of Ashkenazi Jewish ancestry, and—by extension—among women of all ancestries. Most recently, she and her colleagues have succeeded in developing new methods for sequencing DNA and RNA and are using this technology to identify previously undetectable underlying mutations in the study participants’ families.
What she’s learned so far: Dr. King has identified several other genetic causes of breast cancer beyond mutations in the BRCA genes and has developed a new approach for genomic evaluation. For the first time, genomic excision using CRISPR/Cas9 (“CATCH”) with long-read (“SMRT”) genomic sequencing have been integrated to identify small RNA and DNA mutations, a technology Dr. King has named SMRT-CATCH.
What’s next: Dr. King and her team will use SMRT-CATCH to identify cancer-predisposing mutations in breast cancer genes from the most severely affected unsolved families and patients from the NYBCS. The team hypothesizes that the remaining genetic predisposition to inherited breast cancer is due primarily to individually rare, severe, structural mutations in complex genomic regions of breast cancer genes, which SMRT-CATCH will be able to pinpoint.
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.In 2014, she received the Lasker Special Achievement Award for Medical Research and in 2016 the United States National Medal of Science.