Large-scale exome sequencing project aims to accelerate discoveries, save lives

By Susan Murphy

When Michelle Ewy, 38, received an opportunity at Mayo Clinic to get her DNA tested for genetic mutations related to breast and ovarian cancers, and other cancers and diseases, she jumped at the chance. 

"I wasn't thinking much of what the outcome would be because there has not been a prevalence of breast or ovarian cancer history in any of my family members," Michelle recalls from her hobby farm in Iowa, where she spends most weekends with her husband and two young sons. 

But her DNA results showed a BRCA-2 mutation.

Up to 80% of women who have the inherited genetic disorder will develop breast cancer in their lifetime and up to 30% will develop ovarian cancer. Males have an increased risk of developing breast cancer and prostate cancer.

"So my reaction was complete shock," says Michelle. "I spent the next 60 minutes on the phone with a genetic counselor going through what BRCA is; the risks of having this gene mutation; the risks that it poses to me, and to my kids and family members."

After comprehensive genetic counseling at Mayo Clinic, Michelle decided to have a double mastectomy, followed by a hysterectomy two months later, to reduce her risk.  

"I took a fairly aggressive approach, knowing that I have two little boys who I need to be around for and a husband who needs me, as well," says Michelle. "I feel that making the decision to be a participant in this research study has saved my life."

Putting genomics into action

Mayo Clinic is sequencing the exomes of tens of thousands of people from diverse backgrounds to investigate large-scale patterns of distinctive mutations that fuel disease. Exome sequencing analyzes almost all the 20,000 genes that provide instructions for making proteins, which play many critical roles in the body. This is where most known disease-causing mutations occur.

The massive diverse database will provide immediate help to people like Michelle and enable researchers to unlock the secrets of disease and revolutionize patient care for years to come. 

"The potential of this project is immense," says Konstantinos Lazaridis, M.D., the Carlson and Nelson Endowed Executive Director for Mayo Clinic's Center for Individualized Medicine.

"As we know, we are made of genes, proteins, metabolites, exposures," Dr. Lazaridis explains. "This is what defines us as humans in health and disease. So imagine if we can not only understand the gene part, but also our metabolites, our exposures of a lifetime, our proteins ― and how those together interact in a human to create disease or wellness."

The overall goal of the sequencing project is to accelerate discoveries in individualized medicine to tailor prevention, diagnosis and treatment to a patient's unique genetic makeup.  

"Taking all this information, understanding the complexity of this information, and then being able to deliver what we can offer to patients for common and rare disease, for cancer and noncancer, for inflammatory conditions, and elements of aging," he says.

Dr. Lazaridis says detecting inherited genetic diseases early, or even before symptoms have a chance to develop, will save the lives of patients and their family members. 

"This is where knowledge becomes powerful," Dr. Lazaridis says.

Investigating actionable genetic mutations

As Mayo Clinic researchers are investigating volumes of data in pursuit of translational discoveries, research participants are learning if they carry disease-causing mutations.  

"In this particular research study, we are reporting back results for three very specific conditions," explains Teresa Kruisselbrink, a genetic counselor supervisor in Mayo Clinic's Center for Individualized Medicine. 

The conditions include clinically actionable variants for an inherited form of high cholesterol called familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome — a form of hereditary colorectal cancer. An additional subset of focused clinically actionable genetic findings include certain types of hereditary cancers, hereditary heart conditions and severe responses to certain medications.

Teresa and her team of genetic counselors work closely with research participants to help them understand their genetic-related risks, and best prevention screenings and strategies.  

"Some strategies might include having screening earlier in life," Teresa says. "There are also some preventive measures by way of therapies that people can take to reduce their risk." 

Teresa says many participants find the benefits of genetic testing to be immeasurable, but for some, receiving abnormal results can be overwhelming. 

"Genetic information can cause distress. It can cause anger. It certainly can cause guilt, for example, if a person is understanding that they might have passed this on to their children," Teresa says. "That's why we're there for them to help them through that journey of both learning how to deal with their new diagnosis medically as well as how they can go through that journey from a psychosocial standpoint, as well.

'I'm really glad I found out'

Damask Grinnell, 21, joined the research study because she became curious about genetic testing while researching the topic in her biology college course. As an Asian American, she also wanted to add diversity to Mayo Clinic's dataset. She found out she carries a hereditary breast cancer gene, despite no family history.

"I'm really glad that I found out about it now because I can do preventive things and look out for it early instead of waiting until it's too late, and I'm in my 30s with a family and develop breast cancer," says Damask from her home in Rochester, Minnesota. "It gives me peace of mind."

Damask says she will now undergo regular screenings and scans. 

"And now that I know, I can try to get my brother to do genetic testing and my family members," she says. "Since I have the mutation, that gives everybody else an excuse to do it, too." 

Mayo Clinic is working toward a future where genomics will routinely be incorporated into the care of all patients, so physicians can find diseases earlier and treat them more precisely.

To learn more about exome sequencing at Mayo Clinic and the stories of Michelle Ewy and Damask Grinnell, watch this video:

This story was originally published on the Mayo Clinic Center for Individualized Medicine blog.