Alert, avert, advise: how genetic testing is transforming hereditary cancer care

“People think of hereditary cancer as something rare and remarkable,” says Kevin Hughes, a breast cancer expert who recently joined the Hollings Hereditary Cancer Clinic at the Medical University of South Carolina (MUSC) as director of cancer genetics. “But 2% of the population has one of these genes — that’s about seven million people in the United States alone, and we haven’t even found all of them yet.”

Genetic testing used to be costly and time-consuming. Hughes, who was an early adopter of DNA sequencing for detecting breast cancer risk, remembers that 30 years ago, analysing two genes would cost about US$4,000. These costs continued to be high until 2013, when patent changes and advancements in high-throughput DNA sequencing significantly reduced expenses.

“Now, anybody at MUSC over the age of 18 who signs a consent can get their BRCA and Lynch genes tested, as well as for familial hypercholesterolaemia, which causes heart disease,” says Hughes. “We’ve moved away from this idea of genetic testing as something risky and dangerous to something vital for the medical care of the patient.”

To position genetic testing as a key element in all branches of medicine, MUSC has devised a multi-pronged strategy. The Hollings Hereditary Cancer Clinic coordinates precision care for patients with hereditary cancer risk, supported by a genetic counselling team that helps patients work through their concerns and make health-care decisions. And at the population level, an innovative state-wide testing project has enrolled tens of thousands of South Carolinians to gather genetic insights that are being integrated into clinical care and research. Hereditary cancer patients, as well as those at high risk, are among those who stand to benefit from this kind of joined-up genomic approach.

Genetic testing on a new scale

In cancer genetics, germline mutations, which patients are born with, are responsible for hereditary forms of the disease. “I have many patients come in with advanced cancers; we do genetic testing and find out they’re positive [for germline mutations],” says Hughes. “If we’d known that about them 10 years ago, this wouldn’t have happened. We’re not testing nearly enough patients.

“If a person has a cancer of a certain type at a certain age or they have a strong family history, then we test them — that is critical. I strongly recommend testing for everyone who meets the guidelines, and within a few years we’re just going to test everybody.”

Hughes and his colleagues are currently compiling the genetic information of the 84 genes they test, creating customized websites for each medical specialism. These online hubs, which show connections between genes and the organs at risk, could help specialists make decisions based on genes that are important to them. For example, for a urologist, the resource links the kidney to its cancer-causing genes.

In addition to creating the Hollings Hereditary Cancer Clinic, where patients with germline mutations receive care tailored to the type and stage of cancer, MUSC aims to use the power of big data to improve access to personalized health care. In partnership with genomics company Helix, and under the leadership of MUSC professor of medicine Daniel Judge, the hospital launched the state-wide research project In Our DNA South Carolina in 2021. This population health genomic screening project has thus far invited more than 100,000 adults in South Carolina to participate.

The project screens genes for the US Centers for Disease Control (CDC) Tier 1 genomic conditions, which are hereditary breast and ovarian cancer, Lynch-type colorectal cancer, and familial hypercholesterolaemia. The resulting data is being used to improve management of cancer and heart disease, the leading causes of death for adults in the state.

Beyond the CDC Tier 1 conditions, In Our DNA SC aims to increase the use of genetics in clinical practice, such as in pharmacogenomics, where physicians monitor how particular genes impact responses to medication. Another goal is education: getting medical students, residents and non-geneticist medical practitioners to become more familiar with this information and making it easier to access.

Life-saving research

The final component of the programme is research. Genetic material and linked but de-identified electronic medical records are available to all MUSC researchers.

“As we get affordable high-throughput gene sequencing, we’ll be able to identify specific patterns of DNA that correlate with disease and be more aggressive about prevention when we know someone is at highest risk of coronary disease, hypertension or diabetes,” says Judge.

But the research implications go beyond oncology and other prominent therapy areas. According to Judge, In Our DNA SC has enlisted more than 28,000 participants and enabled five new research projects at MUSC since its launch. One project addresses Ehlers-Danlos syndrome, a rare inherited condition that affects connective tissue such as joints, skin, muscle and bones. The syndrome clearly shows genetic causes, but they remain mysterious. Using exome sequencing, MUSC researcher Russell Norris and his team have now identified two families of Ehlers-Danlos syndrome patients with the same variant in the same gene.

The researchers replicated the gene of interest in a mouse model and discovered that the mouse reproduced the phenotype of the syndrome with all the features of hypermobility and joint laxities in elasticity. “We’re hopeful that a genetic answer will provide validation for a lot of patients who carry this diagnosis and for many clinicians who aren’t aware of the disease,” Judge says.

Seeking counsel

To prepare for a wave of participation in genetic testing, MUSC has created a Master’s training programme in genetic counselling. Genetic counsellors help patients gather and analyse family history, discuss how it may affect their risk of a hereditary condition, and then help them decide whether testing is the right move. If a high-risk mutation is identified, they also help patients understand and adapt to that information by planning their future screening and providing emotional support.

“We’re part navigators, part translators,” explains assistant project director Libby Malphrus, who has worked as a clinical genetic counsellor for 22 years. “We bridge the gap between patients, clinicians and the other parts of the health-care team.

“There are countless cases I’ve experienced over the years of people who come in because they’re worried about some condition in their family, many cancer cases where they’ve lost a family member. Having this knowledge truly is power. I’ve had numerous women who’ve lost mothers, sisters, aunts to breast and ovarian cancer and because of testing, they’ve been able to take steps to avoid cancers, and that’s powerful.”