Titles and Affiliations
American Cancer Society Professor
Departments of Medicine and Genome Sciences
Research area
Characterizing the genetic susceptibility to breast cancer in high-risk groups and improving screening and risk stratification strategies.
Impact
The discoveries of BRCA1 and BRCA2 revolutionized breast cancer prevention and treatment. People of Ashkenazi Jewish descent are more likely to carry these mutations than the rest of the population. For many severely affected families, however, no cancer-causing mutations have been found using even the most state-of-the-art technologies. Dr. King is developing a completely new genomic technology that reveals classes of mutations in participants of the New York Breast Cancer Study (NYBCS) that were not detectable by any previous approach. 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.
Progress Thus Far
Dr. King and her team have continued to use a technique called long-read sequencing, which reads DNA and RNA in long, continuous strands rather than in thousands of short fragments, to uncover hidden mutations within the ten genes known to cause inherited breast cancer. This approach can detect mutations that are invisible to standard genetic tests, helping explain inherited risk in some families who previously tested negative through conventional testing. The team has continued studying rare variation near the estrogen receptor gene (ESR1), which plays a central role in breast cancer since many tumors rely on estrogen signaling to grow. This variation doesn’t change the gene’s code, but instead subtly alters how much of the gene’s protein is produced. The team experimentally demonstrated how several of these variants affect ESR1 activity and showed that this altered gene activity is inherited alongside breast cancer risk in severely affected families.
What’s next
Next year, Dr. King and her team will continue to use long-read sequencing to define specific classes of cancer-predisposing mutations that this technology can detect but other approaches miss. They will also investigate, within the Ashkenazi Jewish population, whether inherited regulatory variation near the ESR1 gene influences the age at which breast cancer develops or how severe the disease becomes in people who also carry a BRCA1 or BRCA2 mutation. Together, this work aims to uncover the full range of mechanisms behind inherited breast cancer risk, so more women can learn their genetic risk and take steps to prevent the disease.
Biography
Mary-Claire King, PhD, is the American Cancer Society Professor at the University of Washington, Seattle. She was the first to show that breast cancer is inherited in some families because 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 National Institute of Health (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.
