Genetic Cancer Tests Reveal Uncertain Results - New Science Clarifies the Path to Treatment

Understanding the Evolution of Cancer Treatment

Cancer is fundamentally a genetic disease. It arises when changes in a person's DNA, referred to as variants or mutations, disrupt normal cell functions such as growth and division. These changes can be inherited from families or acquired during a person's lifetime due to factors like smoking, ultraviolet radiation, and infectious agents.

Over the past few decades, we've entered an era of personalised medicine. This approach involves tailoring cancer treatment to each patient's unique characteristics, considering their genetic and molecular make-up, overall health status, age, body composition, lifestyle habits, and use of other medications. As a result, the role of genetics in cancer treatment has become more prominent.

The Role of Genetic Testing in Cancer Care

Advances in DNA sequencing technologies have made it possible to detect genetic variants more quickly and accurately. These tests can look for just a few genes linked to certain medical conditions or describe the entire genome of an individual. DNA sequencing has revolutionised cancer care by enabling doctors to improve prevention, detect cancer early, and select the most appropriate treatment.

In South Africa, the first high-throughput Genomics Centre was launched in 2019 by the South African Medical Research Council. Cancer patients can now undergo whole exome sequencing and whole genome sequencing locally at a cost ranging from R10,000 (about US$566) to R20,000 (about US$1,132). These services are sometimes covered by medical insurance and are also available at research facilities like the Centre for Proteomic and Genomic Research or the Centre for Epidemiological Research and Innovation at Stellenbosch University.

These facilities strengthen the capacity to sequence, analyse, and store human genomes, particularly for the diverse gene pool in Africa. However, routine genome sequencing, especially in the public health sector, remains limited due to high costs, limited awareness, and the need for trained personnel.

Limitations of Genetic Testing

Despite its benefits, genetic testing doesn't always provide clear answers. Not all genetic results are straightforward. In many cases, patients receive results showing changes in their DNA that cannot be confidently classified as either harmful (pathogenic variants) or harmless (benign variants). These unclassified variants are known as variants of uncertain significance.

With the advancement of sequencing technologies, rare or novel variants are more frequently detected. But without a clear understanding of whether the variant affects gene function, clinicians are often forced to wait—sometimes for years—until more information emerges.

When patients undergo genetic testing, often as part of a hereditary cancer screening or in response to early-onset or familial cancers, the hope is to find a variant that clearly explains their condition. However, sequencing may yield variants of uncertain significance, raising questions about its usefulness in patient care and whether the tests are worth the cost.

The Promise of Functional Genomics

Functional genomics is a growing field that could transform how we interpret these unresolved genetic results and improve clinical care for cancer patients. Unlike traditional genetic testing, which simply reads the DNA code, functional genomics investigates how genetic variants behave in biological systems.

By examining how a variant alters gene expression, protein function, cell behaviour, or response to treatments, scientists can determine whether it is likely to be benign or pathogenic. This information is crucial for making timely medical decisions. Importantly, cells derived from patients can be used to mimic real biological conditions more accurately. By comparing cells carrying a variant to those without it, scientists can determine whether the variant influences the response of cells to certain treatments.

In short: genetic testing is like reading the "instruction manual" of a cell. Functional genomics is like testing the effects of changes to these instructions.

A study conducted using patient-derived cells investigated the effects of a rare TP53 variant identified for the first time in germline DNA through whole exome sequencing in a South African family with multiple cancers. The findings showed that this variant made cells resistant to the chemotherapy drug doxorubicin. Instead of undergoing cell death as expected, the cells went into a kind of "sleep mode" called senescence, where damaged cells stop dividing.

Although this prevents the growth of damaged cells, senescent cells can release signals that may inflame and harm nearby healthy cells. The variant also reduced how well immune cells can move, which may affect their ability to go to cancer cells and attack them. This study highlighted how functional genomics can unravel the impact of a variant of uncertain significance, which may guide medical decisions.

The Future of Personalised Medicine

In a world where personalised medicine is rapidly evolving, functional genomics represents a critical step forward, offering more clarity, better care, and renewed hope to those facing cancer.