Every person has some level of risk for developing cancer. What differs from person to person is the level and nature of that risk. 

For some people, that risk is primarily influenced by age and other general risk factors. For others, family history or an inherited genetic variant may substantially increase their likelihood of developing a particular cancer. Increasingly, we are also learning that the combined effects of many genetic differences throughout the genome can influence cancer susceptibility. 

At PreOncology, our goal is to build a platform that helps individuals understand and manage their personal cancer risk while incorporating increasingly sophisticated approaches to early detection. The foundation of that approach is the member’s genomic information. 

Why start with the genome? Because our understanding of cancer risk is continually evolving. The more we learn about how our DNA influences cancer susceptibility, the more opportunities we have to use that information to better understand an individual’s risk. 

That is why PreOncology begins with whole genome sequencing (WGS). 

As a genetic counselor, one of the most important parts of my role is helping people understand what their genetic information can—and cannot—tell us about their health. Genetics can provide powerful information, but it also comes with uncertainty and nuance. My role is to help put those findings into context and translate rapidly evolving science into information that is meaningful for the individual member. 

Our DNA Contains Information About Cancer Risk 

Our DNA contains billions of individual building blocks that provide the biological instructions for how our bodies develop and function. Differences in those building blocks help make each of us unique. Some of those differences can also influence our susceptibility to disease, including cancer. 

There are two broad ways genetic variation can contribute to cancer risk. 

The first involves changes in a single gene that can have a relatively large impact on someone’s risk. These are often called monogenic findings. One of the best-known examples is a pathogenic variant in BRCA1 or BRCA2, which can substantially increase the risk of several cancers, including breast and ovarian cancer, as well as prostate cancer. 

The second involves the combined effects of many genetic differences, each of which may have a relatively small effect on its own. Collectively, these differences can influence disease susceptibility. This is the basis of a polygenic risk score (PRS). 

Think of monogenic risk as one significant piece of information, while polygenic risk considers the combined effect of many smaller genetic differences. Both can contribute to an individual’s overall susceptibility to cancer. 

Importantly, neither type of genetic information determines whether someone will develop cancer. Cancer is complex, and genetic risk is only one part of the picture. Age, family history, environmental exposures, lifestyle, and other biological factors all contribute. 

The goal, therefore, is not to reduce someone’s cancer risk to a genetic number. It is to better understand the different factors contributing to that person’s overall risk and use that information to help inform how their risk can be managed. 

Many cancer centers and genetics clinics offer hereditary cancer risk assessment. This is particularly important for someone who has had cancer at a young age, has had more than one primary cancer, has been diagnosed with a cancer that is uncommon or strongly associated with hereditary risk, or has a family history that suggests a hereditary pattern. 

Typically, the process begins with a genetic counselor. We review the individual’s personal and family history, discuss what genetic testing could tell us, and explore the potential benefits, limitations, and implications of testing before someone decides whether to proceed. 

Traditional hereditary cancer testing has focused primarily on monogenic risk. A laboratory tests a selected group of genes known to be associated with hereditary cancer and looks for variants that may increase cancer risk. 

This approach has been tremendously valuable. It has allowed us to identify thousands of people with inherited cancer predisposition and, in many cases, to use that information to guide more intensive cancer screening and other aspects of medical management. 

But there is an inherent limitation: the test is constrained by what we choose to test. 

If a new cancer-associated gene is discovered after someone completes testing, that person may need additional testing to determine whether they carry a relevant variant. 

This becomes particularly important when we consider what happens after a hereditary cancer test comes back “negative.” 

A Negative Hereditary Cancer Test Is Not the Same as Average Cancer Risk

For someone whose personal or family history strongly suggests hereditary cancer risk, a negative test can be surprisingly complicated. 

A negative result does not necessarily mean there is no genetic contribution to the family’s cancer history. It means that, with the genes and technology evaluated at that time, we did not identify a pathogenic variant that explains the observed history. 

Historically, the next step might be to continue screening based on personal and family history and revisit genetic testing years later as scientific knowledge advances. 

That approach made sense based on the technology available at the time. But it can also create a frustrating experience for patients: another appointment, another blood draw, another test, and potentially another period of uncertainty about what the results mean. 

More importantly, a negative hereditary cancer test does not necessarily mean that a person’s genetic risk is average. It means we did not identify one of the specific high-impact genetic variants we were looking for. 

This distinction is increasingly important as we learn more about polygenic risk. 

The Emerging Role of Polygenic Risk

Over the past several years, research has demonstrated that the combined effects of many common genetic variants can contribute to cancer susceptibility. Polygenic risk scores are designed to capture this combined effect. 

Most people fall somewhere within an expected range of polygenic risk. But because genetic risk exists along a continuum, some individuals have a substantially higher or lower polygenic risk for a particular cancer. 

This creates an important possibility: someone could have no identifiable pathogenic variant in a hereditary cancer gene and still have a genetic profile associated with increased susceptibility to a particular cancer. 

The science is promising, but it is important to be transparent about where the field stands today. Polygenic risk scores are not yet universally recommended for clinical management, and questions remain about how best to incorporate them into healthcare. The evidence for clinical utility varies depending on the cancer and the specific score being used. 

Another important challenge is ancestry. Many early PRSs were developed using research populations that were disproportionately of European genetic ancestry. As a result, some scores may not perform equally well across populations. Researchers are actively working to address this limitation through more diverse datasets and improved approaches to validating and calibrating PRSs. 

This is where the role of the genetic counselor becomes especially important. Genetic information is not simply a collection of results to be delivered to a member. We need to understand the evidence behind a finding, recognize its limitations, consider how it applies to the individual, and communicate what it may—or may not—mean for their care. 

Why PreOncology Starts with Whole Genome Sequencing

At PreOncology, a member’s cancer risk assessment begins with a blood sample used for whole genome sequencing. 

Rather than sequencing only a predetermined list of genes or a limited set of genetic markers, WGS captures information across essentially the entire genome. 

That distinction gives us something valuable: a comprehensive genomic foundation that can evolve as the science evolves. 

From the same underlying genome sequence, we can evaluate established monogenic cancer risk genes. But we can also analyze genetic information more broadly as our understanding of cancer biology advances. 

If researchers identify a new gene associated with inherited cancer risk in the future, having the individual’s genome already sequenced creates the potential to revisit existing genomic data rather than automatically starting over with another blood draw. 

The same principle applies to polygenic risk. As cancer-specific PRSs are developed, validated, refined, and—where appropriate—considered for clinical use, an existing WGS dataset provides the underlying genetic information needed to evaluate new approaches. 

This does not mean that every future discovery will automatically become a clinically actionable result. New findings need to be carefully evaluated, validated, and interpreted before they should influence an individual’s medical care. 

But it does mean that the underlying genomic information is already there. 

Building a Cancer Risk Management Platform That Can Evolve

This is ultimately what makes whole genome sequencing so important to the PreOncology approach. 

We cannot predict what the next important discovery in cancer genetics will be. But we can build a foundation that allows us to respond when those discoveries happen. 

Today, a member’s genome can help us evaluate established hereditary cancer risk and, as the evidence supports it, emerging approaches to polygenic risk. Tomorrow, that same genomic information may be interpreted in ways we cannot yet anticipate. 

This creates a different relationship with genetic testing. Rather than a one-time event—test, receive a result, and move on—the genome becomes a lasting component of an individual’s cancer risk profile. 

At PreOncology, that genomic foundation supports a broader platform for personalized cancer risk management and early detection. Our goal is not to predict whether someone will develop cancer, but to better understand where their risk falls along the spectrum and use that information to inform how their risk can be managed over time. 

As a genetic counselor, that is what I find most exciting. Genetics cannot give us all the answers—but it can give us better questions to ask as the science advances. 

One blood draw provides the genomic foundation. The science will continue to evolve. And PreOncology is being built to evolve with it.