This year’s Genetics Guide focuses on BRCA1 and BRCA2—tumor-suppressing genes that, in normal cells, help stabilize the cell’s DNA and prevent uncontrollable cell growth. Harmful mutations in BRCA genes can lead to increased risk of breast or ovarian cancer in women: About 60 percent of women who inherit either mutation will develop one of these cancers during their lifetimes, compared to 12 percent in the general population. Men with a BRCA gene mutation have a higher risk of developing breast, prostate and skin cancers. While hundreds of cancer-associated BRCA1 and BRCA2 mutations have been documented, three specific mutations, two in the BRCA1 gene and one in the BRCA2 gene, are more prevalent in people of Ashkenazi Jewish ancestry: One out of 40 will inherit a BRCA1 or 2 mutation. Moment explores the fascinating story behind BRCA’s discovery and provides a glimpse into BRCA research, warning signs and treatment.
Genetics Pioneer Mary-Claire King
Interview by Sarah Breger
In 1990, Mary-Claire King discovered the first evidence for the existence of a gene that was associated with breast cancer. The gene she named BRCA changed the way people thought not only about breast cancer but about the genetics of other common cancers and diseases as well. King—a professor of medicine and genetics at the University of Washington—tells Moment about how she became interested in studying inherited cancers, what the letters B-R-C-A signify, and why testing for BRCA mutations should be universal.
How did you become involved in the field of breast cancer genetics?
I got involved by doing what would now be called a post-doc. I had finished my PhD in genetics at Berkeley in 1972, showing that humans and chimpanzees are, genetically, 99 percent identical. I then went with my husband to Chile to teach but was forced to return after the 1973 coup. When I returned to the Bay Area I needed a job and wanted to do something meaningful. This was at the time Nixon had declared “war on cancer,” and there was money set aside to study cancer in-depth. I was delighted to be offered a position in San Francisco with carte blanche to do work on breast cancer. I thought my background in mathematics could transfer nicely to see if and how cancer evolves as it passes from one generation to another in a single family. To prove this, I had to show that this genetic component could be physically mapped on a specific chromosome. It took 17 years, but we identified that the inheritance of a mutated gene increases the risk of breast or ovarian cancer.
Why did you name the gene BRCA?
It’s officially named after Breast Cancer and unofficially after Berkeley, California where I was doing the research. I hoped to name it BROCA after Paul Broca, the 19th-century French neurologist who first suggested studying inherited breast cancer in families in a systematic way, but I was only allowed four letters. Eventually I was able to call a genetic test that could capture and sequence all genes associated with ovarian or breast cancer the BROCA test—my small tribute to him. The gene is actually pronounced B-R-C-A. BRACA (bra-ka) refers to BRACAnalysis, Myriad Genetics’ test for BRCA1 and BRCA2.
Were there many women in genetics research in the 1970s?
There were women, but very few in leadership roles. Leadership in science was very much a man’s preserve. But, that said, I could not have done this without the surgeons—mostly male—who recognized that there were families in which breast cancer was genetically inherited because they were seeing it at their practices all the time. They were very generous and referred patients to me and saw me as potentially being a helpful resource. On the scientific side, I was completely ignored.
Why were you ignored?
What I was doing was iconoclastic. I was coming at the project from a mathematical perspective. At the time, people had done brilliant work on cancer but the dominant theory was that viruses played a role in cancer. Now we know all cancer is genetic.
How is all cancer genetic?
In that all cancer involves changes in DNA. It’s just that for the vast majority those changes are specific to the cell where the cancer begins. I’m interested in families in which those changes are actually inherited from father and mother.
Don’t environmental factors play a role?
About a decade ago, we carried out a study of women of Jewish ancestry in New York who developed breast cancer. We were interested in families with BRCA1 and BRCA2 mutations and tested more than 1,000 breast cancer patients who self-identified as Ashkenazi Jews. We found that among women with BRCA1 and BRCA2 mutations, those born earlier developed breast cancer at older ages. Women born later, even if they were from the same family, more often developed their breast cancer at younger ages. Women who carry BRCA1 and BRCA2 mutations of all generations were also at high risk for ovarian cancer. We asked: Why is this happening? So we looked at other risks leading to breast cancer. Many of these risks involve women’s reproductive lives: the age at which one begins to have a family, the age one begins to menstruate, and body mass and exercise. We found that the women born later tended to begin menstruating earlier, have children later, and tend to be heavier and exercise less. Which is not to say they were overweight or didn’t exercise but just weren’t on their feet all day or walking up six flights of stairs to their apartment like those born in earlier decades. What’s interesting is that all of these changes are associated with well-being, success, more education and better nourishment.
Do men also carry the BRCA gene?
Of course, fathers are where half our genes come from. Although men do not often develop breast cancer and obviously do not develop ovarian cancer. The consequence for breast or ovarian cancer is that even if a woman has no family history of breast cancer on her mother’s side, it does not mean she doesn’t have a BRCA mutation. She may have inherited the mutation from her cancer-free father.
By that logic, do you think all women should get tested for the mutation?
Ideally, yes. And I think every young Jewish woman in her mid-30s should be tested even if she says, “I am not from a family who has breast cancer.” It’s the mutation that matters, not the family history. We can confidently tell women that if they do carry the mutation, they have a particularly high risk and should be aware of their options. The actions one can take are not easy but are life-saving. About one out of every 40 individuals of Ashkenazi Jewish ancestry has a mutation in the BRCA1 or BRCA2 gene, which is much higher than the general population. (One out of every 800 members of the general population has the mutation.) This is just a happenstance of historical demography.
Is it feasible to test all women?
I think it would be a challenge to establish this as policy in America, but it should be done and it now can be. Every time I know or hear of a Jewish woman who developed breast cancer because of a BRCA1 or BRCA2 mutation, I think, “Why didn’t we get the word out earlier?” With testing, we should be able to reduce mortality from ovarian cancer by 30 to 40 percent in one generation and breast cancer by a substantial amount as well. Jewish women should be in the vanguard.
Why do non-Jews in the Southwest have BRCA1 and BRCA2 gene mutations?
Some breast cancer patients in the Southwest have been identified as carrying mutations we recognize as Jewish mutations. Digging deeper, the stories that one hears are very interesting— family lore going back to early colonizing Jews among the Spanish who came to Mexico and intermingled with the populations. These stories fit with the genetics. So it’s not that these mutations are reoccurring in different populations but that the migration of Jews has spread the mutations to different populations. In studying breast cancer genetics, one learns a lot about Jewish migration.
What do you think of the Supreme Court’s June decision that genes cannot be patented? Is there a risk that preventing naturally occurring genes from being patented will hinder breakthroughs?
I’m delighted. There is not a risk of this—that concern arises largely out of people working in the pharmaceutical industry, where drug patents are a completely different issue. Developing a chemo-therapeutic agent is an enormously expensive process from the time of discovery to when it reaches a patient. The drug must go through many rounds of testing and FDA approval. But after the discovery of a gene mutation, genetic diagnosis can begin immediately. All the research and development costs are upfront.
What are you working on now?
I’m working with Ephrat Levy-Lahad from Shaare Zedek Medical Center in Israel and Moien Kanaan at Bethlehem University on the West Bank studying breast cancer in Arab Israeli and Palestinian women in the West Bank, Israel and Gaza. Breast cancer is less frequent in the Palestinian population, which means it is likely that a larger proportion of cases will be due to an inherited predisposition. By studying these women we hope to identify new mutations and genes related to breast cancer.