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Mayo Clinic: New DNA Sequences Hone in on Breast, Ovarian Cancer Risk

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Key Points

  • Researchers studied variations across the genomes of 14,351 BRCA1 mutation carriers and found two new DNA sequences associated with breast cancer risk and two new DNA sequences associated with ovarian cancer risk.
  • In a second study, researchers discovered four new DNA sequences that were associated with ER-negative breast cancer but not ER-positive breast cancer, which may yield new information about the biology of the disease.
  • In the largest genome-wide association study in any cancer to date, researchers found 41 new DNA sequences associated with breast cancer.

Researchers at Mayo Clinic Cancer Center have identified new DNA sequences associated with breast cancer and ovarian cancer. The findings, which appear in three studies in the journals PLoS Genetics and Nature Genetics, will help reveal the underlying causes of these diseases and help researchers build better risk models to support new prevention strategies.

BRCA1 Mutation Carriers

In the first study, published in the journal PLoS Genetics, researchers studied variations across the genomes of 14,351 BRCA1 mutation carriers and found two new DNA sequences that are associated with breast cancer risk and two new DNA sequences associated with ovarian cancer risk. One sequence associated with ovarian cancer is the first known BRCA1-specific risk sequence for the disease. The researchers were then able to use their results to estimate the risks of both cancers for each BRCA1 mutation carrier. These new results may soon be incorporated into clinical management of patients.

"Women with mutated copies of the BRCA1 or BRCA2 gene have markedly increased but highly variable risks of breast and ovarian cancer," said Fergus Couch, PhD, a Mayo Clinic investigator who coauthored the study. "To put this into perspective, a woman with a BRCA1 mutation has about a 65% lifetime risk," said Dr. Couch. "Risk models will help her make decisions by indicating if her true risk is liable to be closer to 90%—in which case she may choose prophylactic surgery—or closer to 40%—in which case frequent monitoring may be most appropriate."

ER-negative Breast Cancer

The second study, published in the journal Nature Genetics, focuses on women susceptible to estrogen receptor (ER)–negative forms of breast cancer. Dr. Couch's team discovered four new DNA sequences that were associated with ER-negative breast cancer but not ER-positive breast cancer. The discovery was based on integrated results from three genome-wide association studies of 6,514 ER-negative breast cancer patients and 41,555 healthy controls.

"Women have a worse prognosis if their tumors are ER-negative because these cells grow more rapidly," says Dr. Couch. "They also have fewer treatment options." He says the new DNA sequences will yield new information about the biology of the disease, which could eventually help researchers develop new treatments.

About one-fourth of all breast cancers are ER-negative, with a higher proportion in younger women and women of African ancestry. ER-negative breast cancers are more aggressive and unresponsive to antiestrogens compared to ER-positive breast cancers, which generally have a better prognosis and are often responsive to antiestrogen therapy.

Largest Genome-wide Association Study

The third study, also published in Nature Genetics, reports the findings of the largest genome-wide association study in any cancer to date. Researchers found 41 new DNA sequences associated with breast cancer. Incorporating the DNA sequences into risk models is expected to significantly improve the ability to predict which women are at greater risk of developing breast cancer.

The researchers, including Dr. Couch and authors from Cambridge University's Centre for Cancer Genetic Epidemiology, integrated information from more than 30,000 breast cancer patients and more than 30,000 healthy controls.

The Mayo studies are part of the Collaborative Oncological Gene-environment Study (COGS), an international research collaboration involving investigators from Europe, Asia, Australia, and North America, which identified 49 new DNA sequences associated with an increased risk for breast cancer, ovarian cancer and prostate cancer. "This was an unprecedented study of genetic and lifestyle factors that involved the genotyping of more than 250,000 individuals by 117 research institutes around the world," said Dr. Couch. "The studies were so large that the results are really trustworthy."

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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