Discoveries
Confronting Conclusion: One Patient’s Inconclusive Cancer Test Drives Research to Better Understand Genetics Among Marginalized Populations
Apr 11, 2024 Nicole Levine
With three bouts of breast cancer beginning in her late 20s, a diagnosis of ovarian cancer and a family history of cancer, Evelyn Victor seemed likely to have a BRCA variant—one of the gene variants known to be linked to multiple cancers. Her genetic test returned an inconclusive result.
“Inconclusive” wasn’t a good enough answer for Evelyn, who was then 57, or for her doctor, B.J. Rimel, MD, medical director of the Cancer Clinical Trials Office at Cedars-Sinai and a gynecologic oncologist. It wasn’t a good enough answer for her genetic counselor, who pressed the testing company to discover why the test was inconclusive.
“Thank God they questioned and they pushed,” said Evelyn, now 65.
A thorough sequencing of her DNA uncovered a relatively large deletion in her DNA, which left nothing for the usual BRCA test to bind to, prompting the inconclusive result. Her providers’ persistence resulted in important answers for Evelyn and her daughter, Kristen Victor. The surprising result also launched a scientific inquiry for investigators at Cedars-Sinai’s Gilda Radner Hereditary Cancers Program who are studying how these cancer-causing variants manifest differently in people of color such as Evelyn, who is Black.
“I’m happy they’re pursuing the research so maybe people in the future won’t be going through the same experiences and tribulations,” Evelyn said. “Maybe there will be an answer for this.”
With the knowledge gained from Evelyn’s DNA sequencing, Kristen, a 33-year-old pre-med student at UCLA, pursued genetic testing and learned she has an 89% chance of developing breast cancer and a 44% chance of developing ovarian cancer. She chose prophylactic surgeries to reduce her risk, an opportunity her mother didn’t have.
Evelyn is facing her seventh bout of cancer, which is untreatable. Her DNA is being used in research to create models that will allow for closer study of rare pathogenic variants like hers.
“What I want people to take from my story is hope,” she said. “When this whole thing started, I asked God to keep me here as long as my kids needed me and just until they knew what they were doing and they had their bearings. I didn’t want them to grow up without me. He kept me here 33 years.”
BRCA: Understanding Structural Variants
Variants in the BRCA1 and BRCA2 genes have long been identified as greatly increasing a person’s risk of breast and ovarian cancer, as well as pancreatic cancer, prostate cancer and melanoma. Women of Ashkenazi Jewish descent are 10 times more likely than women in the general population of the U.S. to carry one of these variants—1 in 40 people of Ashkenazi Jewish descent do so. Among women with these variants, approximately 50 out of 100 will develop breast cancer and 30 out of 100 will develop ovarian cancer by age 70.
“A deletion like Evelyn’s had not been reported before,” said Rimel. “The vast majority of the people who have donated their samples to banks like the Gilda Radner Hereditary Cancer Program are of Eastern European Jewish descent, which is reasonable because we know that’s where these variants tend to occur. But we’re just starting to understand what those variants look like in different populations.”
I’m happy they’re pursuing the research so maybe people in the future won’t be going through the same experiences and tribulations. Maybe there will be an answer for this.”
— Evelyn Victor
Michelle Jones, PhD, assistant professor of Biomedical Sciences and director of the Human Genetics and Genomics Core, is studying structural variants in DNA under an American Cancer Society grant. Typically, pathogenic variants in the BRCA1 or BRCA2 genes cause a change in the DNA sequence, which results in the protein not functioning correctly. In structural variants, the DNA sequence is either deleted (missing), there is an extra copy of it, or it could be in the wrong location in the genome.
Jones and her Cedars-Sinai colleagues Simon Gayther, PhD, director of the Center for Bioinformatics and Functional Genomics, and Paul Pharoah, PhD, professor of Computational Biomedicine, examined DNA data from 13,000 women with ovarian cancer and compared it to DNA data from 40,000 women who did not have ovarian cancer. They also compared it to known ovarian cancer genetic variants.
They found many of the women with ovarian cancer did not have a change in their DNA sequence but did have a structural variant—a deletion or duplication that interrupts the normal function of the gene.
Evelyn made an important contribution to this continuing research: Her DNA has been sequenced and used to create laboratory models—along with samples from women with similar variants—to allow study of these variants and the mechanisms underlying the risk.
“We want to know what exactly the result of that gene variant is. How does it function, and how does that confer risk for breast and ovarian cancer?” Jones said.
Read: Cancer Prognosticator
The team is also working to create a biobank that is reflective of Los Angeles’ Black, Latin and Asian populations.
New technologies that allow scientists to see genes in higher resolution—opening microscopic frontiers to explore—as well as advances in efficiently sequencing the genome are also making study of these variants more feasible.
“We don’t yet have a very strong understanding of how these classes of variants are likely to occur in which populations, but if we can identify them, they can be included in clinical testing,” said Gayther, who holds the Barth Family Chair in Cancer Genetics in honor of Beth Y. Karlan, MD. “We will be much more capable of accurately identifying individualized risk in a precision-health approach across populations of different ancestry. Accurately identifying risk can allow us to tailor a prevention plan that’s just right for the individual, but we need to understand the full spectrum of genetic risk to do that well.”
A Legacy of Hope
“I need you to understand who these people are and who they are to me,” Evelyn said as she recounted nearly 40 years of confronting cancer. She proceeded to explain how she met Rimel back in 2016. Her first appointment with the physician came after hours of waiting on an emergency approval from her insurance that finally came at 5:30 p.m. Evelyn’s advanced ovarian cancer required surgery the next day, and Rimel delayed an overseas trip so she could be there.
“Since that day, she’s part of my family, and she knows that I love her,” Evelyn says. “She loves me back, and we’ve been through a lot.”
Kristen moved home to Inglewood from New York City last year to be with her mother; her older brother Arneaux Victor IV; and her father, Arneaux Victor III. She’s continuing her studies and preparing to apply to medical school. She is interested in cardiology, medicine for substance use disorders and sports medicine.
“I’ve had all this time with my children,” Evelyn said. “I’m extremely proud of them because they’re everything I wanted them to be and more, so I’m happy about that.”