City of Hope scientists are finding that there is more to inherited breast and ovarian cancer risk than BRCA1 and BRCA2 genes alone.
By searching the human genetic map, the team seeks to uncover the factors behind how two major women’s cancers develop. Ultimately, scientists may use the research to develop genetic tests that better predict a woman’s cancer risk or to find new targets for future therapies.
|Susan Neuhausen (Photo by p.cunningham)|
This work could advance efforts to realize personalized medicine — care guided by characteristics unique to each patient.
“The hope is that you can better define which women are at the highest risk and then target them for prevention or for better therapies,” said Susan L. Neuhausen, Ph.D., Morris & Horowitz Families Professor in Cancer Etiology and Outcomes Research.
Less than 1 percent of women are believed to carry harmful mutations in the BRCA1 and BRCA2 genes that increase their likelihood of developing certain cancers. These women account for about 5 to 10 percent of breast cancers and 10 to 15 percent of ovarian cancers.
Often, women with BRCA mutations watch as their mothers, sisters, aunts and cousins battle cancer. A troubling question lingers: Am I next?
Tests that detect the mutations have enabled these women to better understand their risk. Precautionary steps for BRCA mutation carriers include more frequent screening and preventive surgery removing their breasts or ovaries.
Yet uncertainty remains even after testing. Different studies show that BRCA carriers face a range of risk to develop breast cancer from 40 to 87 percent.
“I’ve been studying these women for the past 19 years,” Neuhausen said. “I want to help them be able to make more informed decisions on which clinical options are best for them. They need to know: ‘What is my true risk? Are there preventive things I should be doing?’ If a woman is at 40 percent risk of developing cancer by age 70 compared to 80 percent risk, she might make a different decision on preventative options.”
She and her colleagues believe that other genes help account for the margin in risk estimates, so they turned their attention to a cellular pathway involved in insulin-like growth factor (IGF) signaling.
The protein called IGF helps regulate cell growth as well as apoptosis, the process that causes damaged cells, such as cancerous ones, to destroy themselves.
So far, she and colleagues including Jeffrey N. Weitzel, M.D., chief of the Division of Clinical Cancer Genetics, have identified variations in several genes related to IGF that seem to modify breast cancer risk for women with BRCA mutations.
Neuhausen said the results are preliminary. She is working with a worldwide consortium to look at some of these genes in larger studies. If researchers confirm the results, new genetic tests incorporating these and other genes that have been found could more accurately predict women’s true risk.
Scientists are exploring other mechanisms, too. The California Breast Cancer Research Program recently awarded a grant to Neuhausen and co-investigator Gerd Pfeifer, Ph.D., holder of the Lester M. and Irene C. Finkelstein Chair in Biology.
They want to know how breast cancer risk among BRCA mutation carriers may be influenced by epigenetic changes — changes that control how genes function without altering the sequence of DNA itself.
“Risks involved in developing cancer are complex. There are multiple factors that are part of a larger network,” Neuhausen said. “We have to look at more of a big picture than just underlying genetic variation, because nothing operates in a vacuum.”