Mary-Claire King, PhD

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

The goal of the NYBCS has been to identify the causes of inherited breast cancer among women of European Jewish ancestry, and by extension the causes of inherited breast cancer among women of all ancestries. Using a new method called long-read sequencing, Dr. King has found rare mutations deep within DNA regions that are usually ignored by standard genetic tests. In several families, these hidden mutations disrupted important breast cancer genes, helping explain their inherited risk. She and her team are also studying rare changes near the estrogen receptor gene (ESR1) that may alter how the gene is turned on, offering another clue to why breast cancer develops in certain families.

What’s next

Next year, Dr. King and her team will continue to use long-read sequencing to look for hidden genetic mutations that may raise breast cancer risk but are missed by standard tests. They will study families from New York, Nigeria, Israel, and Palestine to see how often these rare mutations occur, whether they cluster in certain parts of the genome, and how strongly they influence risk. This work will help create better strategies for identifying these mutations worldwide. In addition, the team will study subtle genetic changes near the ESR1 gene to learn whether they affect when breast cancer develops in people who already carry BRCA1 or BRCA2 mutations.