December 1, 2023
December 1, 2023

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The Beach Boys Summer IV: Mary-Claire King and the BRCA Genes

If we review great cancer science arising in California and the Beach Boys, we must include Mary-Claire King. She’s got me rockin’ and a rollin,’ rockin’ and a’reelin,’ Mary-Claire. (OK, Barbara Ann).

She was born in Illinois in 1946 and did her undergraduate degree in mathematics at Carleton College before going to the University of California at Berkeley for graduate work in statistics and then switching to genetics. Her doctoral thesis at Berkeley demonstrated that humans and chimpanzees differed in only 1% of their DNA sequences.

King had a very strong left-wing activist streak. While at Berkeley, she joined the antiwar movement and stopped her scientific work for months. She also took off for a year to work with Ralph Nader helping migrant farm workers. After finishing her PhD, she went to Chile to work in a teaching program, but had to leave because of a military coup against President Salvador Allende. She returned to do a postdoc at the University of California San Francisco with Nick Petrakis, a genetic epidemiologist, which focused on why certain families were so affected by breast cancer. The phenomenon of familial breast cancer was appreciated for over a century, but modern epidemiology was only beginning to address it. It was recognized that the risk was greater if first-degree relatives had the disease (mothers, sisters), the cancer was bilateral (in both breasts), and the cases were premenopausal. At the time, little was known about lifestyle or environmental risk factors, so King concluded that genetics must play some significant role.

This was now the early 1980s; she started by interviewing 1,579 breast cancer patients under age 55 about their family histories. King and her co-workers then analyzed the results using sophisticated mathematical modeling, known as segregation analysis, which investigates how a trait distributes itself and whether its distribution among family members reflects the likelihood of an underlying genetic distribution. Her study, published in the Proceedings of the National Academy of Sciences in 1988, suggested that 4% of the cases reflected an inherited susceptibility, that this was transmitted as an autosomal dominant (you only need to inherit one copy of the gene for it to be expressed), and that those who carried this gene had a lifetime risk of 82% for breast cancer.

But where was this gene located? Today, with modern technology, even a mediocre molecular genetics graduate student could identify this locus in a few weeks. But in the late 1980s, the word “genome” had not yet been coined, and PCR (polymerase chain reaction) and hence fast DNA sequencing had not yet been invented. Thus, for King and colleagues, with the tools they had available, this became a task that took multiple years. The method they used was linkage analysis. Basically, genetic markers had been identified for most of the regions on the 23 chromosomes. One could, therefore, using great effort, map a gene to a certain region on a chromosome by determining that it was found more frequently than in random combination with a certain marker located at that region.

Now back on the faculty at Berkeley, King collected a cohort of 23 large families with 146 cases of breast cancer, and selected breast cancer cases who were young, bilateral and premenopausal and with male breast cancer (another known risk). They looked at 173 genetic markers spread over the 23 chromosomes and computed the probability of co-inheritance of each marker with breast cancer. Ultimately, they found that the risk of early-onset breast cancer mapped to a region on chromosome 17, specifically region 17q21 (published in Science in 1990). She called this gene BRCA for breast cancer (now known as BRCA1).

In 1994, Mark Skolnick at Myriad Genetics was the first to sequence the DNA structure of BRCA1. They went on to identify a host of mutations that were present in those with the disease. In 1994, another group also used linkage analysis to identify a second gene, BRCA2, on chromosome 13, and Myriad Genetics successfully cloned that gene as well, winning patents for both genes. However, in 2013 the Supreme Court ruled that genes could not be patented.

In 1995, King was recruited to the University of Washington in Seattle where she has been since then as professor of genome sciences and medical genetics.

I would be remiss to leave this topic without mentioning that these BRCA genes play a significant role not only for breast cancer and ovarian cancer, but also for prostate cancer, pancreatic cancer and melanoma. Hundreds if not thousands of mutations have been identified for these genes, but several are of particular significance for Ashkenazi Jews and thus make screening in this population a possibility. The studies, statistics and policy guidelines surrounding BRCA prevalence and its testing are complex and would require an article of their own. In the interim, multiple organizations, such as Sharsheret, or the recent outpouring of well-trained genetic counselors at hospitals and cancer centers, should be consulted by readers for guidance for both men and women on this important issue—not just for the initial question of whether and when to test, but for the meaning, significance and follow-up of the results.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

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